Method for calculating molecular strain energy, molecular screening method and related device

Abstract

The application provides a molecular strain energy calculation method, a molecular screening method and related devices. The calculation method comprises the following steps: determining all rotatable dihedral angles of a target molecule based on an initial conformation of the target molecule; performing one-dimensional scanning on each rotatable dihedral angle to obtain a one-dimensional potential energy surface conformation set corresponding to each rotatable dihedral angle; calculating a first energy value of each first conformation in each one-dimensional potential energy surface conformation set to determine a first conformation set corresponding to a local energy minimum point in each one-dimensional potential energy surface conformation set; generating a pseudo two-dimensional scanning conformation set according to the first conformation sets; calculating a second energy value of each pseudo two-dimensional scanning conformation; determining a global energy minimum target conformation in the first conformation sets and the pseudo two-dimensional scanning conformation set according to the first energy value and the second energy value; and determining the strain energy of the target molecule based on an initial energy value of the initial conformation and a target energy value of the target conformation. The application improves the calculation efficiency of the strain energy.

Description

Methods for calculating molecular strain energy, molecular screening methods and related devices Technical Field

[0001] This application relates to the field of computational chemistry, and in particular to methods for calculating molecular strain energy, molecular screening methods, and related apparatus. Background Technology

[0002] Computers are a crucial tool in drug design. They can simulate and predict numerous properties of drug molecules, including solubility, affinity, and pKa. Computer simulations allow for efficient and low-cost screening of drug molecules based on their properties. Among these properties, the strain energy of a drug molecule is an important property of its conformation. Strain energy can be used to determine the likelihood of a drug molecule conformation binding to a protein and to search for lower-energy conformations that may bind to proteins.

[0003] There are two key points in calculating the strain energy of drug molecules: first, how to perform conformational search; and second, how to assess the conformational energy. Conformational search can be achieved in two ways: one is through sampling via molecular dynamics simulations; the other is through direct rotation of the dihedral angles of the molecule to perform the conformational search.

[0004] During their research, the inventors discovered that molecular dynamics simulations often require lengthy simulations and enhanced sampling, consuming significant computational resources. While direct dihedral rotation can more quickly locate low-energy conformations, for drug molecules with numerous rotatable angles, the number of conformations to be evaluated remains enormous, resulting in a large computational burden for strain energy and reducing computational efficiency. Summary of the Invention

[0005] To overcome the problems existing in related technologies, this application provides a method for calculating molecular strain energy, a molecular screening method, and related apparatus to improve the calculation efficiency of strain energy.

[0006] The first aspect of this application provides a method for calculating molecular strain energy, including:

[0007] All rotatable dihedral angles of the target molecule are determined based on its initial conformation;

[0008] A one-dimensional scan is performed on each of the rotatable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles; each set of one-dimensional potential energy surface conformations contains multiple first conformations.

[0009] Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0010] Based on each of the first set of conformations, a set of pseudo-two-dimensional scanning conformations is generated; the set of pseudo-two-dimensional scanning conformations contains multiple pseudo-two-dimensional scanning conformations.

[0011] Calculate the second energy value for each of the pseudo-two-dimensional scanning conformations;

[0012] Based on the first energy value and the second energy value, determine the target conformation with the minimum global energy in each of the first conformation set and the pseudo-two-dimensional scan conformation set;

[0013] The strain energy of the target molecule is determined based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0014] Optionally, it also includes:

[0015] Obtain the molecular force field parameters and variable parameters of the initial conformation of the target molecule;

[0016] Based on the molecular force field parameters and the variable parameters, the initial energy value of the initial conformation is calculated using a preset energy formula.

[0017] Optionally, it also includes:

[0018] Each first conformation in the first conformation set that satisfies the preset elimination condition is eliminated, and the remaining first conformations are used to generate a second conformation set.

[0019] Accordingly, generating a pseudo-two-dimensional scan conformation set based on each of the first conformation sets includes:

[0020] Based on each of the second conformation sets, a pseudo-two-dimensional scan conformation set is generated.

[0021] Optionally, the step of removing first conformations from each set of first conformations that satisfy preset removal conditions includes:

[0022] In each set of first conformations, determine whether there exist two first conformations whose rotatable dihedral rotation angles differ by less than a preset angle value; if so, discard one of the two first conformations; and / or,

[0023] In each set of the first conformations, determine whether there exists a first conformation whose first energy value is greater than the first energy value corresponding to the global energy minimum point in the set of one-dimensional potential energy surface conformations of the first conformation set; if so, remove the first conformation.

[0024] Optionally, calculating the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations includes:

[0025] Constraint optimization is performed on each first conformation in each set of one-dimensional potential energy surface conformations;

[0026] Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations after constraint optimization;

[0027] The target first conformation whose first energy value is lower than the first energy values ​​of the two adjacent first conformations is identified as the local energy minimum point, and a set of first conformations is generated.

[0028] Optionally, generating a pseudo-two-dimensional scan conformation set based on each of the first conformation sets includes:

[0029] Arrange and combine all the first conformations in the first conformation set to generate a pseudo-two-dimensional scan conformation set.

[0030] Optionally, after generating a pseudo-two-dimensional scan conformation set based on each of the first conformation sets, the method further includes:

[0031] Calculate the predicted energy value for each of the pseudo-two-dimensional scanning conformations;

[0032] Based on the predicted energy value, pseudo-two-dimensional scanning conformations that meet the preset conditions are selected;

[0033] Accordingly, calculating the second energy value for each of the pseudo-two-dimensional scan conformations includes:

[0034] For each pseudo-two-dimensional scanning conformation that meets the preset conditions, structural optimization is performed, and the second energy value of each pseudo-two-dimensional scanning conformation after structural optimization is calculated.

[0035] Optionally, the one-dimensional scanning process is as follows:

[0036] Within a preset angle range formed by the first endpoint and the second endpoint, starting from the first endpoint, the rotatable dihedral is rotated by a specified angle in sequence, generating a first configuration with each rotation, until the rotation ends at the second endpoint.

[0037] A second aspect of this application provides a molecular screening method, comprising:

[0038] The strain energy of at least two target molecules is obtained using the method described in any of the preceding methods;

[0039] Select target molecules whose strain energy meets the preset screening conditions from the at least two target molecules as candidate target molecules.

[0040] A third aspect of this application provides a device for calculating molecular strain energy, comprising:

[0041] The first determining unit is used to determine all rotatable dihedral angles of the target molecule based on its initial conformation;

[0042] The first acquisition unit is used to perform a one-dimensional scan on each of the rotatable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles; wherein each set of one-dimensional potential energy surface conformations includes multiple first conformations.

[0043] The second determining unit is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations, so as to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0044] The first generation unit is configured to generate a pseudo-two-dimensional scanning configuration set based on each of the first configuration sets; the pseudo-two-dimensional scanning configuration set includes multiple pseudo-two-dimensional scanning configurations.

[0045] The first computing unit is used to calculate the second energy value of each of the pseudo-two-dimensional scanning conformations;

[0046] The third determining unit is configured to determine the target conformation with the minimum global energy in each of the first conformation sets and the pseudo-two-dimensional scan conformation sets based on the first energy value and the second energy value.

[0047] The fourth determining unit is used to determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0048] A fourth aspect of this application provides a molecular screening device, comprising:

[0049] A strain energy acquisition unit is used to acquire the strain energy of at least two target molecules using the method described above.

[0050] A molecular screening unit is used to select target molecules whose strain energy meets preset screening conditions from the at least two target molecules as candidate target molecules.

[0051] The fifth aspect of this application provides an electronic device, comprising:

[0052] Processor; and

[0053] A memory that stores executable code, which, when executed by the processor, causes the processor to perform the method described above.

[0054] A sixth aspect of this application provides a non-transitory machine-readable storage medium having executable code stored thereon, which, when executed by a processor of an electronic device, causes the processor to perform the method described above.

[0055] The technical solution provided in this application may include the following beneficial effects:

[0056] After determining all rotatable dihedral angles of the target molecule, a set of one-dimensional potential energy surface conformations corresponding to each rotatable dihedral angle is obtained. Each set of one-dimensional potential energy surface conformations includes multiple first conformations. Before determining the strain energy, the first conformations in the set of one-dimensional potential energy surface conformations are screened to select the set of first conformations corresponding to the local energy minimum. Based on the set of first conformations and the pseudo-two-dimensional scanning conformation set generated based on the first conformation set, the target conformation with the global minimum energy is determined. Thus, the strain energy of the target molecule is determined based on the initial energy value of the initial conformation and the target energy value of the target conformation. Therefore, this application utilizes the screened set of first conformations to generate the pseudo-two-dimensional scanning conformation set, greatly reducing the number of pseudo-two-dimensional scanning conformation sets, thereby significantly improving the efficiency of conformation evaluation and thus increasing the computational efficiency of strain energy.

[0057] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and do not limit this application. Attached Figure Description

[0058] The above and other objects, features and advantages of this application will become more apparent from the more detailed description of exemplary embodiments thereof in conjunction with the accompanying drawings, wherein the same reference numerals generally represent the same components in the exemplary embodiments thereof.

[0059] Figure 1 is a flowchart illustrating a method for calculating molecular strain energy provided in Embodiment 1 of this application;

[0060] Figure 2 is a flowchart illustrating a method for calculating molecular strain energy provided in Embodiment 2 of this application;

[0061] Figure 3 is a flowchart illustrating a method for calculating molecular strain energy provided in Embodiment 3 of this application;

[0062] Figure 4 is a flowchart illustrating a method for calculating molecular strain energy provided in Embodiment 4 of this application;

[0063] Figure 5 is a schematic diagram of the structure of a molecular strain energy calculation device provided in Embodiment 1 of this application;

[0064] Figure 6 is a schematic diagram of the structure of a molecular strain energy calculation device provided in Embodiment 2 of this application;

[0065] Figure 7 is a schematic diagram of the structure of a molecular strain energy calculation device provided in Embodiment 3 of this application;

[0066] Figure 8 is a schematic diagram of the structure of an electronic device provided in Embodiment 6 of this application. Detailed Implementation

[0067] Preferred embodiments of the present application will now be described in more detail with reference to the accompanying drawings. While preferred embodiments of the present application are shown in the drawings, it should be understood that the present application may be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to make the present application more thorough and complete, and to fully convey the scope of the present application to those skilled in the art.

[0068] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The singular forms “a,” “the,” and “the” used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0069] It should be understood that although the terms "first," "second," "third," etc., may be used in this application to describe various information, this information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of this application, first information may also be referred to as second information, and similarly, second information may also be referred to as first information. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this application, "multiple" means two or more, unless otherwise explicitly specified.

[0070] Embodiment 1 of this application provides a method for calculating molecular strain energy, as shown in Figure 1. This method may include the following steps:

[0071] Step 101: Determine all rotatable dihedral angles of the target molecule based on its initial conformation;

[0072] In this application, a rotatable dihedral angle is defined as follows: the chemical bond connecting the two central atoms is a single bond, neither of the two central atoms is on a ring, and the two terminal atoms are connected to at least two or more atoms other than the central atoms.

[0073] The initial conformation of the target molecule can be input by the user or obtained directly from the database.

[0074] Optionally, the target molecule mentioned above can be a drug molecule.

[0075] Step 102: Perform a one-dimensional scan on each of the rotatable dihedrals to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedrals;

[0076] Each set of one-dimensional potential energy surface conformations includes a plurality of first conformations generated sequentially by performing a one-dimensional scan of the rotatable dihedral angle.

[0077] A rotatable dihedral angle corresponds to a set of one-dimensional potential energy surface conformations. Assuming N rotatable dihedral angles of the target molecule are determined, then the N rotatable dihedral angles correspond to N sets of one-dimensional potential energy surface conformations. Here, N is a positive integer.

[0078] It should be noted that the one-dimensional scan is performed within a preset angle range, such as a 360° angle range. The rotatable dihedral is rotated by a specified angle at intervals, with the starting end of the range as the reference. The specified angle for each rotation can be the same or different. Each rotation acquires a first configuration, and the rotation ends at the end of the range to cover the preset angle range.

[0079] Specifically, the one-dimensional scanning process is as follows:

[0080] Within a preset angle range formed by the first endpoint and the second endpoint, starting from the first endpoint, the rotatable dihedral is rotated by a specified angle in sequence, generating a first configuration with each rotation, until the rotation ends at the second endpoint.

[0081] The angle values ​​of the first and second endpoints are not limited in this application. Optionally, the angle range formed by the angle values ​​of the first and second endpoints is used to cover 360°. For example, the angle range formed by the first and second endpoints is [-180°, 180°], where the first endpoint is -180° and the second endpoint is 180°. As another example, the angle range formed by the first and second endpoints is [0°, 360°], where the first endpoint is 0° and the second endpoint is 360°.

[0082] This application does not limit the specified angle. The specified angle for each rotation can be the same or different. For example, the specified angle can be any one of 10°, 15°, 20°, or 30°.

[0083] For example, within the angle range of [-180°, 180°], starting from -180°, the rotatable dihedral is rotated sequentially, each time by 10° (i.e., at 10° intervals). Each rotation generates a first conformation, until the rotation reaches 180°, thus generating a total of 36 first conformations.

[0084] Step 103: Calculate the first energy value of each first conformation in each one-dimensional potential energy surface conformation set to determine the first conformation set corresponding to the local energy minimum point in each one-dimensional potential energy surface conformation set.

[0085] Specifically, the first energy value of the first conformation can be calculated using a preset energy formula, which is as follows:

[0086]

[0087] Where E is the energy value of the conformation;

[0088] r is the bond length, r eq k is the equilibrium value of the bond length. r The force constant value is the bond length.

[0089] θ is the bond angle, θ eq k is the equilibrium value of the bond angle. θ The force constant value of the bond angle;

[0090] Let be the value of the dihedral angle, n be the multiplicity of the dihedral angle term, γ be the phase value of the dihedral angle term, and V be the phase value of the dihedral angle term. i The force constant of the dihedral angle;

[0091] R ij The distance between atom i and atom j;

[0092] A ij B ij For the van der Waals parameter value; q i Let q be the charge value of atom i. j ε is the charge value of atom j; ε is the dielectric constant.

[0093] It should be noted that among the parameters mentioned above, the bond length, bond angle, dihedral angle, and distance between atoms i and j are variable parameters. These variable parameters can be determined based on the first conformation.

[0094] The remaining parameters are constants, specifically molecular force field parameters, which can be obtained in advance from the initial conformation of the target molecule based on a molecular force field algorithm. This application does not limit the molecular force field algorithm; any one of GAFF (General Amber Force Field), OPLS (Optimized Potentials for Liquid Simulations), or CGenFF (The CHARMM General Force Field) can be used.

[0095] Each first conformation in a set of one-dimensional potential energy surface conformations corresponds to a first energy value. A local energy minimum point refers to the first conformation in the set of one-dimensional potential energy surface conformations whose energy value is lower than the energy values ​​of its two adjacent first conformations. A set of one-dimensional potential energy surface conformations can contain multiple local energy minimum points, and these local energy minimum points combine to form the set of first conformations.

[0096] Specifically, calculating the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the set of first conformations corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations may include the following process:

[0097] (1.1) Perform constraint optimization on each first conformation in each set of one-dimensional potential energy surface conformations;

[0098] By constraining the first conformation, it is possible to prevent other force field parameters, except for the dihedral angle, from being in a high-energy state, thus affecting the shape of the one-dimensional potential energy surface. Specifically, an optimization algorithm can be used to constrain the first conformation; for example, the CGFR (Conjugate Gradient (Fletcher-Reeves)) algorithm can be used. Constraint optimization here means fixing the angle value of the rotatable dihedral angle at its current value and optimizing the other remaining parameters.

[0099] Specifically, the constraint optimization process is as follows:

[0100] During the one-dimensional scanning process, each time the first conformation is generated, the first conformation is constrained and optimized while maintaining the rotatable dihedral angle at the rotated angle value.

[0101] In this context, the CGFR algorithm refers to the Fletcher-Reeves version of the conjugate gradient algorithm.

[0102] (1.2) Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations after constraint optimization;

[0103] Specifically, the aforementioned preset energy formula can be used to calculate the first energy value of each first conformation after constraint optimization. It should be noted that among the parameters corresponding to the preset energy formula, the bond length, bond angle, dihedral angle, and the distance between atoms i and j are variable parameters. These variable parameters can be obtained after constraining and optimizing the first conformation.

[0104] (1.3) The target first conformation whose first energy value is lower than the first energy value of the two adjacent first conformations is determined as the local energy minimum point, and the first conformation set is generated.

[0105] For example, among the three first conformations generated by rotating to 10°, 20°, and 30° respectively, if the first energy value of the first conformation at 20° is lower than both the first energy value of the first conformation at 10° and the first energy value of the first conformation at 30°, then the first conformation at 20° is a local energy minimum point. Multiple local energy minimum points can be determined from the set of one-dimensional potential energy surface conformations, thus forming a set of first conformations.

[0106] Step 104: Generate a pseudo-two-dimensional scan conformation set based on each of the first conformation sets;

[0107] The pseudo-two-dimensional scanning conformation set includes multiple pseudo-two-dimensional scanning conformations generated according to each first conformation set.

[0108] Optionally, in this embodiment of the application, generating a pseudo-two-dimensional scanning conformation set based on each of the first conformation sets may include: arranging and combining the first conformations in all the first conformation sets to generate a pseudo-two-dimensional scanning conformation set.

[0109] It is important to note that the first conformation in the first conformation set here refers to the local energy minimum point determined from the set of one-dimensional potential energy surface conformations. Each pseudo-two-dimensional scanning conformation includes one first conformation from all the first conformation sets, but the first conformations contained in different pseudo-two-dimensional scanning conformations are not exactly the same. That is, a first conformation is selected from each first conformation set, and these first conformations are combined into a pseudo-two-dimensional scanning conformation, until all the first conformations in all the first conformation sets have been traversed, resulting in multiple pseudo-two-dimensional scanning conformations, thus forming a pseudo-two-dimensional scanning conformation set.

[0110] Assuming there are N rotatable dihedral angles, corresponding to N sets of first conformations, it can be determined that each pseudo-2D scanning conformation includes N first conformations, and these N first conformations come from different sets of first conformations. Furthermore, the first conformations contained in different pseudo-2D scanning conformations are not entirely the same.

[0111] For example, if the target molecule has three rotatable dihedral angles, and the local energy minimum points of the three rotatable dihedral angles are {-180, 0}, {30, 90}, and {20, 50}, then after sorting and combining them, the following pseudo-two-dimensional scanning conformation can be formed:

[0112] Pseudo-2D scanning conformation 1: The angles of the three rotatable surfaces are -180°, 30°, and 20° respectively;

[0113] Pseudo-2D scanning conformation 2: The angles of the three rotatable surfaces are -180°, 30°, and 50° respectively;

[0114] Pseudo-2D scanning conformation 3: The angles of the three rotatable surfaces are -180°, 90°, and 20° respectively;

[0115] Pseudo-2D scanning conformation 4: The angles of the three rotatable surfaces are -180°, 90°, and 50° respectively;

[0116] Pseudo-2D scanning conformation 5: The angles of the three rotatable surfaces are 0, 30, and 20, respectively;

[0117] Pseudo-2D scanning conformation 6: The angles of the three rotatable surfaces are 0, 30, and 50 degrees respectively;

[0118] Pseudo-2D scanning conformation 7: The angles of the three rotatable surfaces are 0, 90, and 20, respectively;

[0119] Pseudo-2D scanning conformation 8: The angles of the three rotatable surfaces are 0, 90, and 50.

[0120] Step 105: Calculate the second energy value for each of the pseudo-two-dimensional scanning conformations;

[0121] When calculating the second energy value of the pseudo-two-dimensional scanning conformation, the preset energy formula mentioned above can be used, wherein the above variable parameters can be determined based on the pseudo-two-dimensional scanning conformation.

[0122] Each pseudo-two-dimensional scanning conformation in the pseudo-two-dimensional scanning conformation set corresponds to a second energy value.

[0123] Step 106: Based on the first energy value and the second energy value, determine the target conformation with the minimum global energy in each of the first conformation sets and the pseudo-two-dimensional scan conformation sets;

[0124] The global minimum energy refers to the minimum energy among the first set of conformations and the pseudo-two-dimensional scan conformations. Specifically, the first conformations in the first set of conformations and the pseudo-two-dimensional scan conformations in the pseudo-two-dimensional scan conformations can be uniformly sorted based on their energy values ​​to determine the target conformation with the minimum global energy.

[0125] Step 107: Determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0126] Specifically, the strain energy of the target molecule is the initial energy value minus the target energy of the target conformation. The strain energy formula is as follows:

[0127] E strain =E init -E min，glb

[0128] E stamin For strain energy, E init E is the initial energy value. mir，gib The target energy value for the target configuration.

[0129] It should be noted that the initial energy value can be calculated using the aforementioned preset energy formula, which will be described in detail later.

[0130] As can be seen, this application uses the first set of screened conformations to generate a pseudo two-dimensional scanning conformation set, which greatly reduces the number of pseudo two-dimensional scanning conformation sets, thereby greatly improving the efficiency of conformation evaluation and thus improving the calculation efficiency of strain energy.

[0131] During their research, the inventors discovered that among the methods for assessing molecular conformational energy mentioned in the background art, quantum chemistry-based methods offer the highest energy assessment, but require enormous computational resources. In contrast, molecular force fields, through empirical equations such as the harmonic oscillator model simulating bond stretching and the point charge model simulating electrostatic interactions, can balance the trade-off between computational accuracy and high computational cost. These empirical equations rely on many empirical parameters, and by adjusting these parameters, molecular force fields can also achieve high accuracy.

[0132] Therefore, in order to improve computational efficiency while ensuring computational accuracy, this application can calculate strain energy by using molecular force fields as a tool for energy assessment and by directly rotating dihedral angles for conformational search. However, for target molecules with a large number of rotatable flexible angles, the number of conformations that need to be evaluated by directly rotating dihedral angles is still enormous. Therefore, this application has further screened these conformations. Specifically, Embodiment 2 of this application provides a method for calculating molecular strain energy, as shown in Figure 2. This method includes the following steps:

[0133] Step 201: Receive the initial conformation of the target molecule;

[0134] Step 202: Obtain the molecular force field parameters and variable parameters of the initial conformation;

[0135] The variable parameters include: bond length, bond angle, dihedral angle, and distance between atoms i and j.

[0136] The molecular force field parameters can be obtained from the initial conformation of the target molecule based on a molecular force field algorithm. This application does not limit the molecular force field algorithm used; any one of GAFF, OPLS, or CGenFF can be used.

[0137] Step 203: Based on the molecular force field parameters and the variable parameters, determine the initial energy value of the initial conformation using a preset energy formula;

[0138] The preset energy formula can be found in the preset energy formula mentioned above. In the above formula, apart from the four variable parameters of bond length, bond angle, dihedral angle, and distance between atoms i and j, the rest are molecular force field parameters.

[0139] Step 204: Determine all rotatable dihedral angles of the target molecule based on its initial conformation;

[0140] Step 205: Perform a one-dimensional scan on each of the rotatable dihedrals to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedrals;

[0141] The set of one-dimensional potential energy surface conformations includes multiple first conformations generated sequentially by performing a one-dimensional scan of the rotatable dihedral angle.

[0142] Step 206: Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the set of first conformations corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0143] Step 207: Generate pseudo-two-dimensional scanning conformations based on each of the first conformation sets;

[0144] Step 208: Calculate the second energy value for each of the pseudo-two-dimensional scanning conformations;

[0145] Step 209: Based on the first energy value and the second energy value, determine the target conformation with the minimum global energy in each of the first conformation sets and the pseudo-two-dimensional scan conformation sets;

[0146] Step 210: Determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0147] As can be seen, this application calculates strain energy by using molecular force field as a tool for energy assessment and by directly rotating dihedral angles to perform conformation search. Furthermore, the conformations are screened, and the first set of screened conformations is used to generate a pseudo-two-dimensional scanning conformation set, which greatly reduces the number of pseudo-two-dimensional scanning conformation sets. This significantly improves the efficiency of conformation assessment, thereby increasing the efficiency of strain energy calculation and ensuring calculation accuracy.

[0148] To further improve the calculation efficiency of strain energy, Embodiment 3 of this application provides a method for calculating molecular strain energy, as shown in Figure 3. This method includes the following steps:

[0149] Step 301: Determine all rotatable dihedral angles of the target molecule based on its initial conformation;

[0150] Step 302: Perform a one-dimensional scan on each of the rotatable dihedrals to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedrals;

[0151] Each of the aforementioned one-dimensional potential energy surface conformations contains multiple first conformations.

[0152] Step 303: Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the set of first conformations corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0153] Step 304: Remove the first conformations that meet the preset removal conditions from each of the first conformation sets, and generate the second conformation set from the remaining first conformations;

[0154] Optionally, the step of removing first conformations from each set of first conformations that satisfy preset removal conditions includes:

[0155] (2.1) In each set of first conformations, determine whether there exist two first conformations whose rotatable dihedral angles have a difference in rotation angle less than a preset angle value; if so, discard one of the two first conformations; and / or,

[0156] (2.2) In each set of the first conformations, determine whether there exists a first conformation whose first energy value is greater than a preset energy value than the first energy value corresponding to the global energy minimum point in the set of one-dimensional potential energy surface conformations of the first conformation; if so, remove the first conformation.

[0157] Wherein, the global minimum point in the set of one-dimensional potential energy surface conformations refers to the first conformation with the smallest first energy value in the set of one-dimensional potential surface conformations. The second conformation set includes the first conformation in the first conformation set that has not been removed.

[0158] In other words, within the first conformation set, if the difference between the rotation angles of the corresponding rotatable dihedrals of two first conformations is within a preset angle value (e.g., 60 degrees), then only one first conformation is retained, and the other is discarded. Alternatively, the first conformation with the lower energy value can be retained, while the first conformation with the higher energy value is discarded. For example, if one first conformation is generated by rotating the corresponding rotatable dihedral by 10 degrees, and another first conformation is generated by rotating the same rotatable dihedral by 50 degrees, the rotation angles of the two first conformations differ by 40 degrees, which is within the preset angle value, then one of the first conformations is deleted. If the energy value corresponding to a first conformation differs from the energy value of the global minimum point in the one-dimensional potential energy surface conformation set corresponding to the first conformation set by a preset energy value (e.g., 6 kcal / mol) or more, then that first conformation is discarded.

[0159] The elimination process achieves a second screening of the set of one-dimensional potential energy surface conformations.

[0160] Step 305: Generate a pseudo-two-dimensional scan conformation set based on each of the second conformation sets;

[0161] Optionally, the first conformations in each second conformation set can be sorted and combined to generate a pseudo-two-dimensional scanning conformation set. This pseudo-two-dimensional scanning conformation set contains multiple pseudo-two-dimensional scanning conformations. Assuming there are N rotatable dihedral angles, there are corresponding N second conformation sets. Therefore, each pseudo-two-dimensional scanning conformation contains N first conformations, which come from different second conformation sets. The first conformations contained in different pseudo-two-dimensional scanning conformations are not entirely the same.

[0162] However, since the number of first conformations in the second conformation set is less than the number of first conformations in the first conformation set, the number of pseudo-two-dimensional scanning conformations generated based on the first conformations in the second conformation set is also much less than the number of pseudo-two-dimensional scanning conformations generated based on the first conformations in the first conformation set.

[0163] Step 305 is a specific implementation of generating a pseudo-two-dimensional scan construction set based on each of the first conformation sets in the previous embodiment.

[0164] Step 306: Calculate the second energy value for each of the pseudo-two-dimensional scanning conformations;

[0165] Step 307: Based on the first energy value and the second energy value, determine the target conformation with the minimum global energy in each of the first conformation sets and the pseudo-two-dimensional scan conformation sets;

[0166] Step 308: Determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0167] As can be seen, this application performs a second screening. First, it selects the first set of conformations corresponding to the local energy minimum point from the one-dimensional potential energy surface conformation set. Then, it removes the first conformations in each of the first conformation sets that meet the preset removal conditions to select the second set of conformations. The second set of conformations is then used to generate a pseudo two-dimensional scanning conformation set. The number of pseudo two-dimensional scanning conformation sets is further reduced through the second screening, which greatly improves the efficiency of conformation evaluation and thus improves the calculation efficiency of strain energy.

[0168] This application can also improve the calculation efficiency of strain energy by screening pseudo-two-dimensional scanning conformations. Specifically, embodiment four of this application provides a method for calculating molecular strain energy, as shown in Figure 4. This method includes the following steps:

[0169] Step 401: Determine all rotatable dihedral angles of the target molecule based on its initial conformation;

[0170] Step 402: Perform a one-dimensional scan on each of the rotatable dihedrals to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedrals;

[0171] Each of the aforementioned one-dimensional potential energy surface conformations contains multiple first conformations.

[0172] Step 403: Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the set of first conformations corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0173] Step 404: Generate a pseudo-two-dimensional scan conformation set based on each of the first conformation sets;

[0174] Optionally, after determining the first conformation set in step 403, the method may further include: removing the first conformations in each of the first conformation sets that meet the preset removal conditions, and generating a second conformation set from the remaining first conformations; correspondingly, step 404 specifically involves: generating a pseudo-two-dimensional scanning conformation set based on each of the second conformation sets.

[0175] Step 405: Calculate the predicted energy value for each of the pseudo-two-dimensional scanning conformations;

[0176] The predicted energy value is the sum of the first energy values ​​of the first conformation contained in the pseudo-two-dimensional scan conformation.

[0177] The formula for predicting energy values ​​is as follows:

[0178]

[0179] Among them, E conf To predict energy values;

[0180] E i，1D Let be the first energy value of the angle corresponding to the i-th dihedral angle on the one-dimensional potential energy surface of the dihedral angle in the pseudo-two-dimensional scanning conformation.

[0181] Step 406: Based on the predicted energy value, select pseudo-two-dimensional scanning conformations that meet the preset conditions;

[0182] The preset conditions in this application can be flexibly set, with the aim of filtering out pseudo-two-dimensional conformations with lower predicted energy values.

[0183] In one implementation, the process of selecting pseudo-two-dimensional scanning configurations that meet preset conditions based on the predicted energy value includes: selecting pseudo-two-dimensional scanning configurations whose predicted energy values ​​are below a preset threshold.

[0184] In another implementation, pseudo-two-dimensional scanning conformations that meet preset conditions are selected based on the predicted energy values, including:

[0185] All pseudo-two-dimensional scanning conformations are sorted from smallest to largest based on the predicted energy value, and the first preset number of pseudo-two-dimensional scanning conformations are selected.

[0186] The preset threshold and preset number can be flexibly set based on the actual situation, and this application does not impose any restrictions.

[0187] Step 407: Perform structural optimization on each pseudo-two-dimensional scanning conformation that meets the preset conditions, and calculate the second energy value of each pseudo-two-dimensional scanning conformation after structural optimization.

[0188] In this embodiment, an optimization algorithm can be used to optimize the structure of the pseudo-two-dimensional scanning conformation. For example, the CGFR algorithm can be used to optimize the structure of the pseudo-two-dimensional scanning conformation. When calculating the second energy value of each pseudo-two-dimensional scanning conformation after structural optimization, the preset energy formula mentioned above can be used, wherein the above-mentioned variable parameters can be obtained after optimizing the structure of the pseudo-two-dimensional scanning conformation.

[0189] Step 408: Based on the first energy value and the second energy value, determine the target conformation with the minimum global energy in each of the first conformation sets and the pseudo-two-dimensional scan conformation sets;

[0190] Step 409: Determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0191] In another embodiment of this application, it may further include:

[0192] The first conformation in the set of one-dimensional potential energy surface conformations and the pseudo-two-dimensional scan conformations in the set of pseudo-two-dimensional scan conformations are uniformly sorted based on their energy values, and the sorted conformations and their corresponding energy values ​​are output for user reference.

[0193] Therefore, in this embodiment, the pseudo-two-dimensional scanning conformation was screened once, further reducing the number of pseudo-two-dimensional scanning conformations, thereby further improving the efficiency of conformation evaluation and increasing the calculation efficiency of strain energy.

[0194] It should be noted that although this embodiment increases the computational load of predicting energy values, the subsequent processing using the selected pseudo-two-dimensional scanning conformation still requires much less computation than the subsequent processing performed directly without selecting the pseudo-two-dimensional scanning conformation.

[0195] To better demonstrate the beneficial effects of this application, the inventors selected three target molecules of different sizes, with 4, 7, and 10 rotatable dihedral angles, respectively.

[0196] The methods described in Embodiment 1 (Method 1), Embodiment 3 (Method 2), and the method based on quantitative energy assessment from related technologies (Method 3) were used to evaluate the actual calculated strain energy and its value. See Table 1 below for reference:

[0197] Table 1

[0198]

[0199] As can be seen from Table 1 above, if Method 3 is used as the reference standard, the strain energy value calculated by this application is not much different from it, but it can greatly save calculation time. Furthermore, if the local energy minimum point is further screened (corresponding to Method 2), the calculation efficiency can be further improved. Please note that in Method 3, when the number of dihedral angles is 10, the calculation process takes too long, and the specific values ​​of calculation time and strain energy are not shown here.

[0200] This application provides a molecular screening method in embodiment five, comprising:

[0201] The strain energy of at least two target molecules is obtained using a molecular strain energy calculation method provided in any of the above embodiments; target molecules whose strain energy meets preset screening conditions are selected from the at least two target molecules as candidate target molecules.

[0202] The preset screening conditions are not limited in this application. For example, target molecules with strain energies greater than a preset first strain energy can be selected from at least two target molecules as candidate target molecules, or target molecules with strain energies less than a preset second strain energy can be selected from at least two target molecules as candidate target molecules. The values ​​of the preset first and second strain energies can be set based on actual conditions, and are not limited in this application. Alternatively, multiple target molecules can be sorted according to their strain energies, and the target molecules at the top of the sorted list (e.g., 10%, 20%) can be selected as candidate target molecules.

[0203] Corresponding to the method for calculating molecular strain energy provided in the preceding method embodiments, the present application also provides a molecular strain energy calculation device, electronic device, and storage medium. Several device embodiments are briefly described below.

[0204] Embodiment 1 of this application provides a molecular strain energy calculation device, as shown in FIG5. The device includes: a first determining unit 110, a first acquiring unit 120, a second determining unit 130, a first generating unit 140, a first calculating unit 150, a third determining unit 160, and a fourth determining unit 170; wherein:

[0205] The first determining unit 110 is used to determine all rotatable dihedral angles of the target molecule based on the initial conformation of the target molecule;

[0206] In this application, a rotatable dihedral angle is defined as follows: the chemical bond connecting the two central atoms is a single bond, neither of the two central atoms is on a ring, and the two terminal atoms are connected to at least two or more atoms other than the central atoms.

[0207] The first acquisition unit 120 is used to perform a one-dimensional scan on each of the selectable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles.

[0208] Each of the one-dimensional potential energy surface sets includes a plurality of first conformations sequentially generated by performing a one-dimensional scan of the selectable dihedral angles.

[0209] The one-dimensional scanning process is as follows:

[0210] Within a preset angle range formed by the first endpoint and the second endpoint, starting from the first endpoint, the rotatable dihedral is rotated by a specified angle in sequence, generating a first configuration with each rotation, until the rotation ends at the second endpoint.

[0211] The second determining unit 130 is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations, so as to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0212] Each first conformation in a set of one-dimensional potential energy surfaces corresponds to a first energy value. A local energy minimum point refers to the first conformation in the set of one-dimensional potential energy surface conformations whose energy value is lower than the energy values ​​of its two adjacent first conformations. A set of one-dimensional potential energy surface conformations can contain multiple local energy minimum points, and these local energy minimum points combine to form the set of first conformations.

[0213] Optionally, in this embodiment of the application, the second determining unit 130 may include:

[0214] The first optimization module is used to perform constraint optimization on each first conformation in each set of one-dimensional potential energy surface conformations.

[0215] The first calculation module is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations after constraint optimization.

[0216] The first generation module is used to determine the target first conformation whose first energy value is lower than the first energy value of the two adjacent first conformations as the local energy minimum point, and generate the first conformation set.

[0217] The constraint optimization process of the first optimization module is as follows:

[0218] During the one-dimensional scanning process, each time the first conformation is generated, the first conformation is constrained and optimized while maintaining the rotatable dihedral angle at the rotated angle.

[0219] Specifically, the first calculation module can be used to calculate the first energy value of the first conformation using a preset energy formula, and the preset energy formula can be referred to the description of the method embodiment, which will not be repeated here.

[0220] The first generation unit 140 generates pseudo-two-dimensional scanning conformations based on each of the first conformation sets;

[0221] The pseudo-two-dimensional scanning conformation set contains multiple pseudo-two-dimensional scanning conformations.

[0222] In this embodiment of the application, the first generation unit 140 can be specifically used to arrange and combine the first conformations in all the first conformation sets to generate a pseudo two-dimensional scanning conformation set.

[0223] The second acquisition unit 150 is used to calculate the second energy value of each of the pseudo-two-dimensional scanning conformations;

[0224] Each pseudo-two-dimensional scanning conformation in the pseudo-two-dimensional scanning conformation set corresponds to a second energy value.

[0225] Specifically, the second acquisition unit 150 can use a preset energy formula to calculate the second energy value of the pseudo-two-dimensional scanning conformation.

[0226] The third determining unit 160 is configured to determine the target conformation with the minimum global energy in each of the first conformation set and the pseudo-two-dimensional scan conformation set based on the first energy value and the second energy value.

[0227] The global minimum energy refers to the minimum energy in the first conformation set and the pseudo-two-dimensional scan conformation set.

[0228] Specifically, the third determining unit 160 can uniformly sort the first conformation in the first conformation set and the pseudo two-dimensional scan conformation in the pseudo two-dimensional scan conformation set based on energy values, thereby determining the target energy value with the minimum global energy.

[0229] The fourth determining unit 170 is used to determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0230] Specifically, the initial energy value minus the target energy value is the strain energy of the target molecule. It should be noted that the initial energy value can be calculated using the aforementioned preset energy formula.

[0231] As can be seen, this application uses the first set of screened conformations to generate a pseudo two-dimensional scanning conformation set, which greatly reduces the number of pseudo two-dimensional scanning conformation sets, thereby greatly improving the efficiency of conformation evaluation and thus improving the calculation efficiency of strain energy.

[0232] Embodiment 2 of this application provides a molecular strain energy calculation device, as shown in FIG6. The device includes: a second acquisition unit 180, a fifth determination unit 190, a first determination unit 110, a first acquisition unit 120, a second determination unit 130, a first generation unit 140, a first calculation unit 150, a third determination unit 160, and a fourth determination unit 170; wherein:

[0233] The third acquisition unit 180 is used to acquire the molecular force field parameters and variable parameters of the initial conformation of the target molecule;

[0234] The variable parameters include: bond length, bond angle, dihedral angle, and distance between atoms i and j.

[0235] The molecular force field parameters can be obtained from the initial conformation of the target molecule based on the molecular force field algorithm.

[0236] The fifth determining unit 190 is used to determine the initial energy value of the initial conformation based on the molecular force field parameters and the variable parameters using a preset energy formula.

[0237] The preset energy formula can refer to the preset energy formula mentioned above. In the above formula, apart from the four variable parameters of bond length, bond angle, dihedral angle, and distance between atoms i and j, the rest are molecular force field parameters.

[0238] The first determining unit 110 is used to determine all rotatable dihedral angles of the target molecule based on the initial conformation of the target molecule;

[0239] The first acquisition unit 120 is used to perform a one-dimensional scan on each of the rotatable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles.

[0240] Each of the aforementioned one-dimensional potential energy surface conformations includes multiple first conformations.

[0241] The second determining unit 130 is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations, so as to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0242] The first generation unit 140 is used to generate a pseudo-two-dimensional scan conformation set based on each of the first conformation sets;

[0243] The pseudo-two-dimensional scanning conformation set includes multiple pseudo-two-dimensional scanning conformations;

[0244] The first computing unit 150 is used to calculate the second energy value of each of the pseudo-two-dimensional scanning conformations;

[0245] The third determining unit 160 is configured to determine the target conformation with the minimum global energy in each of the first conformation set and the pseudo-two-dimensional scan conformation set based on the first energy value and the second energy value.

[0246] The fourth determining unit 170 is used to determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0247] As can be seen, this application calculates strain energy by using molecular force field as a tool for energy assessment and by directly rotating dihedral angles to perform conformation search. Furthermore, the conformations are screened, and the first set of screened conformations is used to generate a pseudo-two-dimensional scanning conformation set, which greatly reduces the number of pseudo-two-dimensional scanning conformation sets. This significantly improves the efficiency of conformation assessment, thereby increasing the efficiency of strain energy calculation and ensuring calculation accuracy.

[0248] This application provides a device for calculating molecular strain energy in embodiment three, as shown in Figure 7. The device includes: a first determining unit 110, a first acquiring unit 120, a second determining unit 130, a first eliminating unit 210, a first generating unit 140, a first calculating unit 150, a third determining unit 160, and a fourth determining unit 170, wherein:

[0249] The first determining unit 110 is used to determine all rotatable dihedral angles of the target molecule based on the initial conformation of the target molecule;

[0250] The first acquisition unit 120 is used to perform a one-dimensional scan on each of the rotatable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles.

[0251] Each of the aforementioned one-dimensional potential energy surface conformations includes multiple first conformations.

[0252] The second determining unit 130 is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations, so as to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations.

[0253] The first elimination unit 210 is used to eliminate the first conformations that meet the preset elimination conditions in each of the first conformation sets, and the remaining first conformations generate the second conformation set.

[0254] The preset rejection criteria include:

[0255] In the first conformation set, if the difference between the rotation angles of the rotatable dihedrals corresponding to two first conformations is within a preset angle value (e.g., 60 degrees), then only one first conformation is retained and the other first conformation is discarded; and / or, if the energy value corresponding to a first conformation differs from the energy value of the global energy minimum point in the one-dimensional potential energy surface conformation set corresponding to the first conformation set by a preset energy value (e.g., 6 kcal / mol) or more, then that first conformation is discarded.

[0256] Specifically, the first rejection unit 210 may include a first rejection module and / or a second rejection module, wherein:

[0257] The first elimination module is used to determine in each set of first conformations whether there are two first conformations whose rotation angles of the selectable dihedral angles are less than a preset angle value; if so, one of the two first conformations is eliminated.

[0258] The second elimination module is used to determine in each of the first conformations set whether there exists a first conformation whose first energy value is greater than a preset energy value than the first energy value corresponding to the global energy minimum point in the one-dimensional potential energy surface conformation set corresponding to the first conformation; if so, the first conformation is eliminated.

[0259] Wherein, the global minimum point in the set of one-dimensional potential energy surface conformations refers to the first conformation with the smallest first energy value in the set of one-dimensional potential surface conformations. The second conformation set includes the first conformation in the first conformation set that has not been removed. The first generation unit 140 is used to generate pseudo-two-dimensional scanning conformations based on each of the second conformation sets.

[0260] Optionally, the first generation unit 140 can be used to arrange and combine the first conformations in each of the second conformation sets to generate pseudo-two-dimensional scanning conformations.

[0261] The first computing unit 150 is used to calculate the second energy value of each of the pseudo-two-dimensional scanning conformations;

[0262] The third determining unit 160 is configured to determine the target conformation with the minimum global energy in each of the first conformation set and the pseudo-two-dimensional scan conformation set based on the first energy value and the second energy value.

[0263] The fourth determining unit 170 is used to determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

[0264] As can be seen, this application performs a second screening. First, it selects the first set of conformations corresponding to the local energy minimum point from the one-dimensional potential energy surface conformation set. Then, it removes the first conformations in each of the first conformation sets that meet the preset energy removal conditions, and selects the second set of conformations. The second set of conformations is then used to generate a pseudo two-dimensional scanning conformation set. The number of pseudo two-dimensional scanning conformation sets is further reduced through the second screening, which greatly improves the efficiency of conformation evaluation and thus improves the calculation efficiency of strain energy.

[0265] This application provides a device for calculating molecular strain energy in embodiment four. Based on any of the above device embodiments, it further includes: a second calculation unit and a first screening unit, wherein:

[0266] The second calculation unit is used to calculate the predicted energy value of each of the pseudo-two-dimensional scanning conformations.

[0267] The first screening unit is used to screen out pseudo-two-dimensional scanning conformations that meet preset conditions based on the predicted energy value.

[0268] In one implementation, the first filtering unit is specifically used to filter out pseudo-two-dimensional scanning configurations whose predicted energy values ​​are below a preset threshold. In another implementation, the first filtering unit is specifically used to sort all pseudo-two-dimensional scanning configurations based on their predicted energy values ​​from smallest to largest, and select the first preset number of pseudo-two-dimensional scanning configurations.

[0269] The preset threshold and preset number can be flexibly set based on the actual situation, and this application does not impose any restrictions.

[0270] Accordingly, the first computing unit mentioned in the previous device embodiment is specifically used to perform structural optimization on each pseudo-two-dimensional scanning conformation that meets the preset conditions, and to calculate the second energy value of each pseudo-two-dimensional scanning conformation after structural optimization.

[0271] In another embodiment of the apparatus in this application, it may further include:

[0272] The first output unit is used to uniformly sort the first conformation in the one-dimensional potential energy surface conformation set and the pseudo-two-dimensional scan conformation in the pseudo-two-dimensional scan conformation set based on the energy value, and output the sorted conformations and the corresponding energy values.

[0273] Therefore, in this embodiment, the pseudo-two-dimensional scanning conformation was screened once, further reducing the number of pseudo-two-dimensional scanning conformations, thereby further improving the efficiency of conformation evaluation and increasing the calculation efficiency of strain energy.

[0274] It should be noted that although this embodiment increases the computational load of predicting energy values, the subsequent processing using the selected pseudo-two-dimensional scanning conformation still requires much less computation than the subsequent processing performed directly without selecting the pseudo-two-dimensional scanning conformation.

[0275] This application provides a molecular screening device in embodiment five, comprising: a strain energy acquisition unit and a molecular screening unit;

[0276] Among them, the strain energy acquisition unit is used to obtain the strain energy of at least two target molecules using a molecular strain energy calculation method described above.

[0277] A molecular screening unit is used to select target molecules whose strain energy meets preset screening conditions from the at least two target molecules as candidate target molecules.

[0278] The preset screening conditions are not limited in this application. For example, target molecules with strain energies greater than a preset first strain energy can be selected from at least two target molecules as candidate target molecules, or target molecules with strain energies less than a preset second strain energy can be selected from at least two target molecules as candidate target molecules. The values ​​of the preset first and second strain energies can be set based on actual conditions, and are not limited in this application. Alternatively, multiple target molecules can be sorted according to their strain energies, and the target molecules at the top of the sorted list (e.g., 10%, 20%) can be selected as candidate target molecules.

[0279] Regarding the apparatus in the above embodiments, the specific manner in which each module performs its operation has been described in detail in the embodiments related to the method, and will not be elaborated further here.

[0280] Figure 8 is a schematic diagram of the structure of an electronic device according to Embodiment Six of this application. Referring to Figure 8, the electronic device 1000 includes a memory 1010 and a processor 1020.

[0281] The processor 1020 can be a Central Processing Unit (CPU), or other general-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc. The general-purpose processor can be a microprocessor or any conventional processor.

[0282] Memory 1010 may include various types of storage units, such as system memory, read-only memory (ROM), and permanent storage devices. ROM may store static data or instructions required by the processor 1020 or other modules of the computer. Permanent storage devices may be read-write storage devices. Permanent storage devices may be non-volatile storage devices that retain stored instructions and data even when the computer is powered off. In some embodiments, permanent storage devices use mass storage devices (e.g., magnetic or optical disks, flash memory) as permanent storage devices. In other embodiments, permanent storage devices may be removable storage devices (e.g., floppy disks, optical drives). System memory may be a read-write storage device or a volatile read-write storage device, such as dynamic random access memory. System memory may store some or all of the instructions and data required by the processor during operation. Furthermore, memory 1010 may include any combination of computer-readable storage media, including various types of semiconductor memory chips (DRAM, SRAM, SDRAM, flash memory, programmable read-only memory), and disks and / or optical disks may also be used. In some embodiments, memory 1010 may include a removable storage device that is readable and / or writable, such as a laser disc (CD), a read-only digital multifunction optical disc (e.g., DVD-ROM, dual-layer DVD-ROM), a read-only Blu-ray disc, an ultra-high density optical disc, a flash memory card (e.g., SD card, mini SD card, Micro-SD card, etc.), a magnetic floppy disk, etc. Computer-readable storage media do not contain carrier waves or transient electronic signals transmitted wirelessly or via wired connections.

[0283] The memory 1010 stores executable code, which, when processed by the processor 1020, can cause the processor 1020 to execute part or all of the methods described above.

[0284] The solution of this application has been described in detail above with reference to the accompanying drawings. In the above embodiments, the descriptions of each embodiment have different emphases; parts not described in detail in a certain embodiment can be referred to in the relevant descriptions of other embodiments. Those skilled in the art should also understand that the actions and modules involved in the specification are not necessarily essential to this application. Furthermore, it is understood that the steps in the method of this application embodiment can be adjusted, combined, and deleted according to actual needs, and the modules in the device of this application embodiment can be combined, divided, and deleted according to actual needs.

[0285] Furthermore, the method according to this application can also be implemented as a computer program or computer program product, which includes computer program code instructions for performing some or all of the steps in the method described above.

[0286] Alternatively, this application may be implemented as a non-transitory machine-readable storage medium (or computer-readable storage medium, or machine-readable storage medium) storing executable code (or computer program, or computer instruction code) that, when executed by a processor of an electronic device (or electronic device, server, etc.), causes the processor to perform some or all of the steps of the methods described above according to this application.

[0287] Those skilled in the art will also understand that the various exemplary logic blocks, modules, circuits, and algorithm steps described in connection with the present application can be implemented as electronic hardware, computer software, or a combination of both.

[0288] The flowcharts and block diagrams in the accompanying drawings illustrate the architecture, functionality, and operation of possible implementations of systems and methods according to various embodiments of this application. In this regard, each block in a flowchart or block diagram may represent a module, segment, or portion of code containing one or more executable instructions for implementing the specified logical function. It should also be noted that in some alternative implementations, the functions marked in the blocks may occur in a different order than those marked in the drawings. For example, two consecutive blocks may actually be executed substantially in parallel, and they may sometimes be executed in reverse order, depending on the functions involved. It should also be noted that each block in the block diagrams and / or flowcharts, and combinations of blocks in the block diagrams and / or flowcharts, can be implemented using a dedicated hardware-based system that performs the specified function or operation, or using a combination of dedicated hardware and computer instructions.

[0289] The various embodiments of this application have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or improvement of the technology in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A method for calculating molecular strain energy, characterized in that, include: All rotatable dihedral angles of the target molecule are determined based on its initial conformation; A one-dimensional scan is performed on each of the rotatable dihedral angles to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedral angles; each set of one-dimensional potential energy surface conformations contains multiple first conformations. Calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations; generate a pseudo-two-dimensional scanning conformation set based on all the first conformation sets; the pseudo-two-dimensional scanning conformation set contains multiple pseudo-two-dimensional scanning conformations; calculate the second energy value of each pseudo-two-dimensional scanning conformation; and determine the target conformation with the global minimum energy in each set of first conformations and the pseudo-two-dimensional scanning conformation set based on the first energy value and the second energy value. The strain energy of the target molecule is determined based on the initial energy value of the initial conformation and the target energy value of the target conformation.

2. The method according to claim 1, characterized in that, Also includes: Obtain the molecular force field parameters and variable parameters of the initial conformation of the target molecule; based on the molecular force field parameters and variable parameters, calculate the initial energy value of the initial conformation using a preset energy formula.

3. The method according to claim 1, characterized in that, Also includes: Each set of first conformations that meets the preset elimination conditions is eliminated, and the remaining first conformations are used to generate a second conformation set; correspondingly, generating a pseudo two-dimensional scan conformation set based on all the first conformation sets includes generating a pseudo two-dimensional scan conformation set based on all the second conformation sets.

4. The method according to claim 3, characterized in that, The step of removing a first conformation from each set of first conformations that meets a preset removal condition includes: determining whether there exists a first conformation in each set of first conformations whose difference between the rotation angles of the rotatable dihedrals corresponding to the two first conformations is less than a preset angle value; if so, removing one of the two first conformations; and / or determining whether there exists a first conformation in each set of first conformations whose difference between the first energy value of the first conformation and the first energy value corresponding to the global energy minimum point in the set of one-dimensional potential energy surface conformations corresponding to the first conformation is greater than a preset energy value; if so, removing the first conformation.

5. The method according to claim 1, characterized in that, The step of calculating the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the first conformation set corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations includes: performing constraint optimization on each first conformation in each set of one-dimensional potential energy surface conformations; calculating the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations after constraint optimization; determining the target first conformation whose first energy value is lower than the first energy values ​​of the two adjacent first conformations as the local energy minimum point, and generating the first conformation set.

6. The method according to claim 1, characterized in that, The step of generating a pseudo-two-dimensional scanning conformation set based on all the first conformation sets includes: arranging and combining the first conformations in all the first conformation sets to generate a pseudo-two-dimensional scanning conformation set.

7. The method according to any one of claims 1-6, characterized in that, After generating a set of pseudo-two-dimensional scanning conformations based on all the first conformation sets, the method further includes: calculating the predicted energy value of each pseudo-two-dimensional scanning conformation; filtering out pseudo-two-dimensional scanning conformations that meet preset conditions based on the predicted energy value; correspondingly, calculating the second energy value of each pseudo-two-dimensional scanning conformation includes: performing structural optimization on each pseudo-two-dimensional scanning conformation that meets the preset conditions, and calculating the second energy value of each pseudo-two-dimensional scanning conformation after structural optimization.

8. The method according to any one of claims 1-6, characterized in that, The one-dimensional scanning process is as follows: within a preset angle range formed by the first endpoint and the second endpoint, starting from the first endpoint, the rotatable dihedral is rotated by a specified angle in sequence, generating a first configuration each time it is rotated, until the second endpoint is reached.

9. A molecular screening method, characterized in that, include: The strain energy of at least two target molecules is obtained by using the method described in any one of claims 1-8; Select target molecules whose strain energy meets the preset screening conditions from the at least two target molecules as candidate target molecules.

10. A device for calculating molecular strain energy, characterized in that, include: The first determining unit is used to determine all rotatable dihedral angles of the target molecule based on its initial conformation; A first acquisition unit is used to perform a one-dimensional scan on each of the rotatable dihedrals to obtain a set of one-dimensional potential energy surface conformations corresponding to each of the rotatable dihedrals; wherein each set of one-dimensional potential energy surface conformations includes multiple first conformations; a second determination unit is used to calculate the first energy value of each first conformation in each set of one-dimensional potential energy surface conformations to determine the set of first conformations corresponding to the local energy minimum point in each set of one-dimensional potential energy surface conformations; a first generation unit is used to generate a pseudo-two-dimensional scan conformation set based on all the first conformation sets; the pseudo-two-dimensional scan conformation set includes multiple pseudo-two-dimensional scan conformations; a first calculation unit is used to calculate the second energy value of each pseudo-two-dimensional scan conformation; a third determination unit is used to determine the target conformation with the global minimum energy in each set of first conformations and the pseudo-two-dimensional scan conformation set based on the first energy value and the second energy value; a fourth determination unit is used to determine the strain energy of the target molecule based on the initial energy value of the initial conformation and the target energy value of the target conformation.

11. A molecular screening device, characterized in that, include: A strain energy acquisition unit is used to acquire the strain energy of at least two target molecules using the method described in any one of claims 1-8; A molecular screening unit is used to select target molecules whose strain energy meets preset screening conditions from the at least two target molecules as candidate target molecules.

12. An electronic device, characterized in that, include: processor; And a memory having executable code stored thereon, which, when executed by the processor, causes the processor to perform the method as described in any one of claims 1-9.

13. A non-transitory machine-readable storage medium having executable code stored thereon, which, when executed by a processor of an electronic device, causes the processor to perform the method as described in any one of claims 1-9.

Images