Small molecule substance screening method and device based on nuclear magnetic resonance data

Abstract

The embodiment of the invention provides a small molecule substance screening method and device based on nuclear magnetic resonance data, and relates to the technical field of data processing.The method comprises the steps that a nuclear magnetic spectrum obtained after a nuclear magnetic experiment is conducted on a sample is obtained, and the nuclear magnetic experiment is a CPMG experiment or a WaterLOGSY experiment; according to the chemical shift corresponding to the small molecule substance, detecting a spectrum peak corresponding to the small molecule substance in a nuclear magnetic experiment spectrum; under the condition that the nuclear magnetic experiment is a CPMG experiment, judging whether the small molecule substance interacts with the target protein or not according to the intensity change of the spectrum peak corresponding to the small molecule substance; and under the condition that the nuclear magnetic experiment is a WaterLOGSY experiment, judging whether the micromolecular substance interacts with the target protein or not according to the condition of 180-degree inversion of a spectrum peak corresponding to the micromolecular substance or not. By applying the scheme provided by the embodiment of the invention, the labor cost consumed during small molecule substance screening can be saved.

Description

Technical Field

[0001] The present application relates to the field of data processing technology, and in particular to a method and device for screening small molecule substances based on nuclear magnetic resonance data. Background Art

[0002] In the related art, when using nuclear magnetic resonance technology to screen small molecules as drugs, small molecules that may be able to interact with target proteins are usually selected from an existing large-scale small molecule library, the selected small molecules and the target protein are configured into samples, and then nuclear magnetic resonance experiments are carried out on a nuclear magnetic resonance spectrometer. The nuclear magnetic resonance data obtained from the nuclear magnetic resonance experiment are manually processed and analyzed to select potential small molecules that interact with the target protein.

[0003] However, when conducting large-scale screening of small molecules, the number of samples that need to be processed by the NMR spectrometer may reach hundreds or thousands, and the amount of NMR data generated is huge. Manual processing of the above data consumes a lot of labor costs, and requires staff to have professional knowledge of NMR, and also has certain knowledge requirements for staff. Summary of the invention

[0004] The purpose of the embodiment of the present application is to provide a method and device for screening small molecule substances based on nuclear magnetic resonance data, so as to save the labor cost consumed in the screening of small molecule substances. The specific technical solution is as follows:

[0005] In a first aspect, the present invention provides a method for screening small molecule substances based on nuclear magnetic resonance data, the method comprising:

[0006] Obtaining a nuclear magnetic resonance spectrum obtained after performing a nuclear magnetic resonance experiment on the sample, wherein the nuclear magnetic resonance experiment is a CPMG experiment or a WaterLOGSY experiment, and the sample contains a target protein and a small molecule substance to be screened;

[0007] According to the chemical shift corresponding to the small molecule substance, detecting the change of the spectral peak corresponding to the small molecule substance in the nuclear magnetic resonance experimental spectrum;

[0008] In the case where the NMR experiment is the CPMG experiment, judging whether the small molecule interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule;

[0009] When the NMR experiment is the WaterLOGSY experiment, whether the small molecule interacts with the target protein is determined based on whether the spectral peak corresponding to the small molecule is reversed by 180 degrees.

[0010] In one embodiment of the present application, when the NMR experiment is the CPMG experiment, the sample further comprises a calibration substance that does not interact with the target protein, and the obtaining of the NMR experiment spectrum obtained after performing the NMR experiment on the sample comprises:

[0011] Obtain a reference H spectrum obtained after performing a nuclear magnetic resonance experiment on the sample;

[0012] Obtaining a CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample;

[0013] The step of detecting the change of the spectral peak corresponding to the small molecule substance in the nuclear magnetic resonance experimental spectrum according to the chemical shift corresponding to the small molecule substance comprises:

[0014] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental nuclear magnetic resonance spectrum;

[0015] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum;

[0016] Calculating a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak;

[0017] Calculating a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak;

[0018] For each first spectrum peak, the intensity decrease ratio corresponding to the first spectrum peak is calculated, wherein the intensity decrease ratio is: the ratio of the decrease amplitude of the second ratio of the target second spectrum peak compared to the first ratio of the first spectrum peak to the second ratio, and the target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak;

[0019] The step of judging whether the small molecule substance interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule substance comprises:

[0020] If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substance are greater than a preset ratio, it is determined that the small molecule substance interacts with the target protein.

[0021] In one embodiment of the present application, when the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the obtaining of the nuclear magnetic resonance spectrum obtained after performing the nuclear magnetic resonance experiment on the sample includes:

[0022] Obtain the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample;

[0023] The step of judging whether the small molecule substance interacts with the target protein according to whether the spectrum peak corresponding to the small molecule substance has a 180-degree reversal includes:

[0024] When there is a spectral peak at the chemical shift corresponding to the small molecule in the WaterLOGSY experimental spectrum and the spectral peak is reversed by 180 degrees, it is determined that the small molecule interacts with the target protein.

[0025] In one embodiment of the present application, the step of obtaining a nuclear magnetic resonance spectrum obtained after performing a nuclear magnetic resonance experiment on the sample includes:

[0026] Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples;

[0027] The nuclear magnetic resonance spectrum data is subjected to preset data processing to obtain a nuclear magnetic resonance experimental spectrum, wherein the preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

[0028] In a second aspect, an embodiment of the present application provides a small molecule substance screening device based on nuclear magnetic resonance data, the device comprising:

[0029] A nuclear magnetic resonance experiment spectrum acquisition module is used to obtain a nuclear magnetic resonance experiment spectrum obtained after performing a nuclear magnetic resonance experiment on a sample, wherein the nuclear magnetic resonance experiment is a CPMG experiment or a WaterLOGSY experiment, and the sample contains a target protein and a small molecule substance to be screened;

[0030] A peak detection module, used to detect changes in the peaks corresponding to the small molecule in the nuclear magnetic resonance experimental spectrum according to the chemical shift corresponding to the small molecule;

[0031] A first judgment module is used to judge whether the small molecule substance interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule substance when the nuclear magnetic resonance experiment is the CPMG experiment;

[0032] The second judgment module is used to judge whether the small molecule substance interacts with the target protein according to whether the spectrum peak corresponding to the small molecule substance undergoes a 180-degree reversal when the nuclear magnetic resonance experiment is the WaterLOGSY experiment.

[0033] In one embodiment of the present application, when the NMR experiment is the CPMG experiment, the sample further comprises a calibration substance that does not interact with the target protein, and the NMR experiment spectrum acquisition module is specifically used to:

[0034] Obtain a reference H spectrum obtained after performing a nuclear magnetic resonance experiment on the sample;

[0035] Obtaining a CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample;

[0036] The spectrum peak detection module is specifically used for:

[0037] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental nuclear magnetic resonance spectrum;

[0038] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum;

[0039] Calculating a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak;

[0040] Calculating a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak;

[0041] For each first spectrum peak, the intensity decrease ratio corresponding to the first spectrum peak is calculated, wherein the intensity decrease ratio is: the ratio of the decrease amplitude of the second ratio of the target second spectrum peak compared to the first ratio of the first spectrum peak to the second ratio, and the target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak;

[0042] The first judgment module is specifically used to:

[0043] If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substance are greater than a preset ratio, it is determined that the small molecule substance interacts with the target protein.

[0044] In one embodiment of the present application, when the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the nuclear magnetic resonance experiment spectrum acquisition module is specifically used to:

[0045] Obtain the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample;

[0046] The second judgment module is specifically used to:

[0047] When there is a spectral peak at the chemical shift corresponding to the small molecule in the WaterLOGSY experimental spectrum and the spectral peak is reversed by 180 degrees, it is determined that the small molecule interacts with the target protein.

[0048] In one embodiment of the present application, the NMR experiment spectrum acquisition module is specifically used to:

[0049] Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples;

[0050] The nuclear magnetic resonance spectrum data is subjected to preset data processing to obtain a nuclear magnetic resonance experimental spectrum, wherein the preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

[0051] In a third aspect, an embodiment of the present application provides an electronic device, including a processor, a communication interface, a memory, and a communication bus, wherein the processor, the communication interface, and the memory communicate with each other through the communication bus;

[0052] Memory, used to store computer programs;

[0053] The processor is used to implement any method step described in the first aspect when executing a program stored in the memory.

[0054] In a fourth aspect, an embodiment of the present application provides a computer-readable storage medium, wherein the computer-readable storage medium stores a computer program, and when the computer program is executed by a processor, any method step described in the first aspect is implemented.

[0055] In a fifth aspect, an embodiment of the present application further provides a computer program product comprising instructions, which, when executed on a computer, enables the computer to execute any of the method steps described in the first aspect above.

[0056] Beneficial effects of the embodiments of the present application:

[0057] The method for screening small molecules based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the nuclear magnetic resonance experimental spectrum obtained by performing CPMG experiment or WaterLOGSY experiment on the sample, determines the change of the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. For the CPMG experiment, the embodiment of the present application determines whether the small molecule interacts with the target protein based on the change in the intensity of the spectral peak corresponding to the small molecule. For the WaterLOGSY experiment, the embodiment of the present application determines whether the small molecule interacts with the target protein based on the detection of whether the spectral peak corresponding to the small molecule is reversed by 180 degrees. The scheme provided in the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the CPMG experiment and the WaterLOGSY experiment, thereby completing the screening of small molecules without the need to invest a large number of staff with professional knowledge. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other embodiments can also be obtained based on these drawings.

[0059] Figure 1 A schematic diagram of the first small molecule screening method based on nuclear magnetic resonance data provided in an embodiment of the present application;

[0060] Figure 2 A schematic diagram of a second method for screening small molecules based on nuclear magnetic resonance data provided in an embodiment of the present application;

[0061] Figure 3 A schematic diagram of a process for screening small molecule substances based on CPMG experimental data provided in an embodiment of the present application;

[0062] Figure 4 A schematic diagram of a third method for screening small molecule substances based on nuclear magnetic resonance data provided in an embodiment of the present application;

[0063] Figure 5 A schematic diagram of a process for screening small molecule substances based on WaterLOGSY NMR experimental data provided in an embodiment of the present application;

[0064] Figure 6 A schematic diagram of the structure of a small molecule substance screening device based on nuclear magnetic resonance data provided in an embodiment of the present application;

[0065] Figure 7 A schematic diagram of the structure of an electronic device provided in an embodiment of the present application. DETAILED DESCRIPTION

[0066] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application belong to the scope of protection of the present application.

[0067] Since the related art has the problem that manual analysis of NMR data consumes a lot of labor costs and requires high professional knowledge of the staff, in order to solve the above problems, the embodiment of the present application provides a small molecule substance screening method and device based on NMR data.

[0068] See also Figure 1, is a schematic diagram of the first small molecule substance screening method based on nuclear magnetic resonance data provided in an embodiment of the present application, including the following steps S101-S104.

[0069] S101: Obtaining a nuclear magnetic resonance spectrum obtained after performing a nuclear magnetic resonance experiment on a sample.

[0070] Among them, the above-mentioned NMR experiment is a CPMG (Carr–Purcell–Meiboom–Gill) experiment or a WaterLOGSY (Water-Ligand Observed via Gradient Spectroscopy) experiment, and the above-mentioned samples contain target proteins and small molecules to be screened.

[0071] Specifically, one or more small molecules can be mixed with the target protein to obtain a sample. When multiple small molecules are mixed with the target protein, there should be an interval of at least a preset value between the chemical shifts corresponding to the various small molecules to prevent the chemical shifts corresponding to different small molecules from being similar, resulting in the spectral peak positions corresponding to the small molecules in the nuclear magnetic resonance data obtained after the experiment being close, causing the spectral peaks to interfere with each other and cause confusion.

[0072] In one embodiment of the present application, the small molecule substance and the target protein can be dissolved in a solvent (e.g., water) at a ratio of 20:1 to 30:1 of the concentration of the small molecule substance and the concentration of the target protein to prepare a sample. The prepared sample is placed on an automatic sample injector of a nuclear magnetic spectrometer, and the magnetic field strength of the nuclear magnetic spectrometer can be 600 MHz or above corresponding to the H atomic nuclear magnetic resonance frequency.

[0073] In another embodiment of the present application, the nuclear magnetic resonance experimental spectrum can be generated by following steps A-B.

[0074] Step A: Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples.

[0075] NMR experiments are carried out in the NMR spectrometer system, including reference one-dimensional H spectrum, CPMG experiment or WaterLOGSY experiment. After the NMR experiment, data is automatically collected for each sample to obtain the NMR spectrum data of each sample. A reference one-dimensional H spectrum experiment can obtain a reference H spectrum, a CPMG experiment can obtain a CPMG experimental NMR spectrum, and a WaterLOGSY experiment can obtain a WaterLOGSY experimental spectrum.

[0076] Step B: performing preset data processing on the above-mentioned nuclear magnetic resonance spectrum data to obtain a one-dimensional spectrum.

[0077] The preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

[0078] Specifically, the above-mentioned Fourier transform, phase adjustment, and baseline correction can be implemented based on methods in related technologies, which will not be described in detail here.

[0079] If the NMR experiment is a CPMG experiment, the one-dimensional H spectrum output by the NMR spectrometer is the reference H spectrum, and the collected NMR experimental spectrum is the CPMG experimental NMR spectrum. If the above NMR experiment is a WaterLOGSY experiment, the one-dimensional H spectrum output by the NMR spectrometer is the reference H spectrum, and the collected NMR experimental spectrum is the WaterLOGSY experimental spectrum.

[0080] S102: According to the chemical shift corresponding to the small molecule substance, detecting the change of the spectral peak corresponding to the small molecule substance in the NMR experimental spectrum.

[0081] Specifically, the chemical shift corresponding to a small molecule may be one or more. Theoretically, there will be spectral peaks at the chemical shifts corresponding to the small molecule in the NMR experimental spectrum.

[0082] In one embodiment of the present application, it is possible to detect whether the value of the data at the chemical shift corresponding to a small molecule is greater than the value of the data at all other positions within a preset range of the nuclear magnetic resonance experimental spectrum centered on the position of the chemical shift. If so, it is determined that a spectral peak exists at the chemical shift.

[0083] In another embodiment of the present application, the values ​​of each position in the NMR experimental spectrum can be determined in sequence to determine whether the position of the chemical position is a turning point where the value changes from gradually increasing to gradually decreasing. If so, there is a spectral peak at the chemical shift.

[0084] Alternatively, the spectral peak at the chemical shift in the above-mentioned NMR experimental spectrum may be detected by any method of determining the peak in the relevant technology, and this embodiment of the present application is not limited to this.

[0085] S103: In the case where the NMR experiment is the CPMG experiment, judging whether the small molecule interacts with the target protein according to the intensity change of the spectral peak corresponding to the small molecule.

[0086] The intensity of the peak in the CPMG experimental NMR spectrum will decrease compared to the intensity of the peak in the reference H spectrum. Therefore, in one embodiment of the present application, for a small molecule, the intensity of the peak in the reference H spectrum at each chemical shift corresponding to the small molecule can be compared with the intensity of the peak at the same chemical shift in the CPMG experimental NMR spectrum to obtain the decrease ratio of the peak intensity. If the decrease ratio of the peak at each chemical shift corresponding to a small molecule is greater than the preset ratio, it can be determined that the small molecule interacts with the target protein.

[0087] Other examples of processing CPMG experimental results in this application can be found below Figure 2 As shown, no further details are given here.

[0088] S104: In the case where the NMR experiment is the WaterLOGSY experiment, judging whether the small molecule interacts with the target protein is based on whether the spectral peak corresponding to the small molecule undergoes a 180-degree reversal.

[0089] Theoretically, there should be a spectral peak at the chemical shift corresponding to the small molecule in the nuclear magnetic resonance spectrum generated after the WaterLOGSY experiment. In one embodiment of the present application, if a 180-degree reversal of part or all of the spectral peaks is detected at the chemical shift corresponding to the small molecule, it can be further detected whether the detected spectral peak is caused by an interference signal. If it is not caused by an interference signal, it is determined that the small molecule interacts with the above-mentioned target protein.

[0090] In one embodiment of the present application, the shape of the interference signal may be preset, and the shape of the detected spectrum peak may be compared with the shape of the preset interference signal. If the shape similarity between the two is greater than the preset similarity, the spectrum peak is determined to be an interference signal.

[0091] In another embodiment of the present application, when the intensity of the spectrum peak is greater than a preset intensity, it can be determined that the spectrum peak is an interference signal.

[0092] Other examples of processing WaterLOGSY experimental results in this application can be found below Figure 4 As shown, no further details are given here.

[0093] As can be seen from the above, the small molecule screening method based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the nuclear magnetic resonance experimental spectrum obtained by performing CPMG experiment or WaterLOGSY experiment on the sample, determines the change of the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. For the CPMG experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the change in the intensity of the spectral peak corresponding to the small molecule. For the WaterLOGSY experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the detection of whether the spectral peak corresponding to the small molecule is reversed by 180 degrees. The scheme provided by the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the CPMG experiment and the WaterLOGSY experiment, thereby completing the screening of small molecules without the need to invest a large number of staff with professional knowledge.

[0094] See also Figure 2 , which is a schematic diagram of the second method for screening small molecules based on NMR data provided in an embodiment of the present application. When the NMR experiment is the CPMG experiment, the sample also contains a calibration substance that does not interact with the target protein. The concentration of the calibration substance in different samples is constant. The chemical shift corresponding to the calibration substance is different from the chemical shift of all small molecules to be detected, and will not interfere with the spectral peak of the small molecules to be detected. The corresponding spectral peak can be used as a control for the spectral peak of the small molecules to be detected. In one embodiment of the present application, the calibration substance can be DSS (2,2-Dimethyl-2-silapentane-5-sulfonic acid), which is a water-soluble substance. When heavy water (D2O) is used as a solvent, the chemical shift is calibrated.

[0095] With the aforementioned Figure 1 Compared with the embodiment shown in the figure, the above step S101 can be implemented by the following steps S101A-S101B, the above step S102 can be implemented by the following steps S102A-S102E, and the above step S103 can be implemented by the following steps S103A. Figure 2 The embodiment shown is applied to the context of a CPMG experiment and is therefore similar to Figure 1 By contrast, step S104 does not exist.

[0096] S101A: Obtain a reference H spectrum obtained after performing an NMR experiment on the sample.

[0097] S101B: Obtain the CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample.

[0098] S102A: Detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental NMR spectrum according to the chemical shifts corresponding to the small molecule substance and the calibration substance.

[0099] The method of detecting the first spectrum peak and the first standard spectrum peak is similar to the description of step S102 above, and will not be repeated here.

[0100] S102B: Detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum according to the chemical shifts corresponding to the small molecule substance and the calibration substance.

[0101] The method of detecting the second spectrum peak and the second standard spectrum peak is similar to the description of step S102 above, and will not be repeated here.

[0102] S102C: Calculate a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak.

[0103] In one embodiment of the present application, when there are multiple first spectral peaks, regardless of whether the multiple first spectral peaks correspond to the same small molecule substance, the first ratio of the intensity of each first spectral peak to the intensity of the first standard spectral peak can be uniformly calculated to obtain a first relative spectral peak intensity list.

[0104] S102D: Calculate a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak.

[0105] In one embodiment of the present application, when there are multiple second spectrum peaks, regardless of whether the multiple second spectrum peaks correspond to the same small molecule substance, the second ratio of the intensity of each second spectrum peak to the intensity of the second standard spectrum peak can be uniformly calculated to obtain a second relative spectrum peak intensity list. Theoretically, the number of second spectrum peaks is the same as the number of first spectrum peaks.

[0106] S102E: For each first spectrum peak, calculate the intensity reduction ratio corresponding to the first spectrum peak.

[0107] Among them, the above-mentioned intensity decrease ratio is: the ratio of the decrease range of the second ratio of the target second spectrum peak compared with the first ratio of the first spectrum peak and the second ratio. The above-mentioned target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak.

[0108] S103A: If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substances are greater than a preset ratio, it is determined that the small molecule substances interact with the target protein.

[0109] For example, the above preset ratio is 40%, 50%, etc.

[0110] As can be seen from the above, the method for screening small molecules based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the nuclear magnetic resonance data obtained by the CPMG experiment on the sample, automatically converts the nuclear magnetic resonance data into the CPMG experimental nuclear magnetic spectrum, and then determines the spectral peak corresponding to the small molecule substance according to the chemical shift corresponding to the small molecule substance. In the embodiment of the present application, the intensity of the spectral peak of the small molecule substance in the CPMG experimental nuclear magnetic spectrum and the reference H spectrum is used to determine whether the small molecule substance interacts with the target protein. Thus, the screening of small molecules can be completed without the need to invest a large number of staff with professional knowledge.

[0111] See also Figure 3 , is a flow chart of a small molecule substance screening method based on CPMG experimental data provided in an embodiment of the present application, including the following steps S301-S307.

[0112] S301: Acquire a range of NMR data to be processed.

[0113] The above range may be input by the user or preset.

[0114] S302: Acquire and perform preset data processing on the NMR data within the range, read the processed data, and obtain a reference H spectrum and a CPMG experimental NMR spectrum.

[0115] S303: Read the second peak in the reference H spectrum according to the chemical shift of the small molecule substance.

[0116] S304: Divide the intensity of the second spectrum peak by the intensity of the second standard spectrum peak in the reference H spectrum to obtain a second ratio, and generate a second relative spectrum peak intensity list containing the second ratio.

[0117] S305: reading the first peak in the CPMG NMR experimental spectrum according to the chemical shift of the small molecule substance, dividing the intensity of the first peak by the intensity of the first standard peak in the CPMG NMR experimental spectrum to obtain a first ratio, and generating a first relative peak intensity list including the first ratio.

[0118] S306: Compare the first relative spectrum peak intensity list with the second relative spectrum peak intensity list to determine whether the first ratio of the first spectrum peak decreases by more than 50% relative to the second ratio.

[0119] The above-mentioned first ratio and second ratio may be referred to as relative strengths.

[0120] If not, it means that no small molecule substance interacting with the target protein is detected, and the process returns to step S302 to continue processing the data obtained after the next group of samples are tested.

[0121] If yes, it indicates that there are small molecules that interact with the target protein, and step S307 is executed.

[0122] S307: Determine the small molecule substance that interacts with the target protein and output the detection result.

[0123] Afterwards, the process returns to step S302 to continue processing the data obtained after conducting experiments on the next group of samples.

[0124] See also Figure 4 , which is a schematic diagram of a third method for screening small molecules based on nuclear magnetic resonance data provided in an embodiment of the present application. When the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the step S101 can be implemented by the following step S101C, and the step S104 can be implemented by S104A. Figure 4 The embodiment shown is applied to the scenario of WaterLOGSY experiment and is therefore similar to Figure 1 By contrast, step S103 does not exist.

[0125] S101C: Get the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample.

[0126] S104A: When there is a peak at the chemical shift corresponding to the small molecule in the above-mentioned WaterLOGSY experimental spectrum and the peak is reversed by 180 degrees, it is determined that the above-mentioned small molecule interacts with the above-mentioned target protein.

[0127] Specifically, the data output by the nuclear magnetic spectrometer can be multiplied by -1 to obtain a flipped WaterLOGSY experimental spectrum. If there is a spectral peak at the chemical shift corresponding to the small molecule substance in the flipped WaterLOGSY experimental spectrum, it is determined that there is a spectral peak at the chemical shift corresponding to the small molecule substance in the WaterLOGSY experimental spectrum and the spectral peak is reversed 180 degrees.

[0128] If there are spectral peaks at all chemical shifts corresponding to the above small molecule substances and the spectral peaks are reversed by 180 degrees, it means that the spectral peaks appear at the chemical shifts corresponding to the small molecule substances and are not affected by interference signals, indicating that the small molecule substances interact with the target protein. Otherwise, it means that the small molecule substances do not interact with the target protein.

[0129] As can be seen from the above, the small molecule screening method based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the WaterLOGSY experimental spectrum obtained by performing a WaterLOGSY experiment on the sample, determines the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. If the spectral peak corresponding to the small molecule is detected and a 180-degree reversal occurs, it is determined that the small molecule interacts with the target protein. The scheme provided in the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the WaterLOGSY experiment, thereby completing the screening of small molecules without the need for a large number of staff with professional knowledge.

[0130] See also Figure 5 , is a flow chart of a method for screening small molecule substances based on WaterLOGSY experimental data provided in an embodiment of the present application, including the following steps S501-S507.

[0131] S501: Acquire a range of NMR data to be processed.

[0132] S502: Acquire and perform preset data processing on the nuclear magnetic resonance data within the range, and read the processed data.

[0133] S503: Multiply the processed data by -1 to obtain an inverted WaterLOGSY experimental spectrum.

[0134] S504: Search for peaks in the WaterLOGSY experimental spectrum according to the chemical shift of the small molecule.

[0135] S505: Determine whether a spectrum peak is found.

[0136] If so, execute step S506, otherwise, execute step S502 to continue processing the data obtained after the next group of samples are tested.

[0137] S506: Determine whether the spectrum peak is caused by an interference signal.

[0138] If not, execute step S507; if so, execute step S502 to continue processing the data obtained after the next group of samples are tested.

[0139] S507: Output the detection result.

[0140] Corresponding to the aforementioned small molecule substance screening method based on nuclear magnetic resonance data, the embodiment of the present application also provides a small molecule substance screening device based on nuclear magnetic resonance data.

[0141] See also Figure 6, is a schematic diagram of the structure of a small molecule substance screening device based on nuclear magnetic resonance data provided in an embodiment of the present application, the device comprising:

[0142] The NMR experiment spectrum acquisition module 601 is used to acquire the NMR experiment spectrum obtained after performing a NMR experiment on the sample, wherein the NMR experiment is a CPMG experiment or a WaterLOGSY experiment, and the sample contains a target protein and a small molecule substance to be screened;

[0143] A spectrum peak detection module 602 is used to detect changes in spectrum peaks corresponding to the small molecule substance in the nuclear magnetic resonance experimental spectrum according to the chemical shift corresponding to the small molecule substance;

[0144] A first judgment module 603 is used to judge whether the small molecule substance interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule substance when the nuclear magnetic resonance experiment is the CPMG experiment;

[0145] The second judgment module 604 is used to judge whether the small molecule interacts with the target protein according to whether the spectrum peak corresponding to the small molecule has a 180-degree reversal when the NMR experiment is the WaterLOGSY experiment.

[0146] As can be seen from the above, the small molecule screening method based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the experimental spectrum obtained by performing CPMG experiment or WaterLOGSY experiment on the sample, determines the change of the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. For the CPMG experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the intensity change of the spectral peak corresponding to the small molecule. For the WaterLOGSY experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the detection of whether the spectral peak corresponding to the small molecule is reversed by 180 degrees. The scheme provided by the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the CPMG experiment and the WaterLOGSY experiment, thereby completing the screening of small molecules without the need to invest a large number of staff with professional knowledge.

[0147] In one embodiment of the present application, when the NMR experiment is the CPMG experiment, the sample further comprises a calibration substance that does not interact with the target protein, and the NMR experiment spectrum acquisition module 601 is specifically used to:

[0148] Obtain a reference H spectrum obtained after performing a nuclear magnetic resonance experiment on the sample;

[0149] Obtaining a CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample;

[0150] The spectrum peak detection module 602 is specifically used for:

[0151] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental nuclear magnetic resonance spectrum;

[0152] According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum;

[0153] Calculating a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak;

[0154] Calculating a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak;

[0155] For each first spectrum peak, the intensity decrease ratio corresponding to the first spectrum peak is calculated, wherein the intensity decrease ratio is: the ratio of the decrease amplitude of the second ratio of the target second spectrum peak compared to the first ratio of the first spectrum peak to the second ratio, and the target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak;

[0156] The first determination module 603 is specifically configured to:

[0157] If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substance are greater than a preset ratio, it is determined that the small molecule substance interacts with the target protein.

[0158] As can be seen from the above, the method for screening small molecules based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the nuclear magnetic resonance data obtained by the CPMG experiment on the sample, automatically converts the nuclear magnetic resonance data into the CPMG experimental nuclear magnetic spectrum, and then determines the spectral peak corresponding to the small molecule substance according to the chemical shift corresponding to the small molecule substance. In the embodiment of the present application, the intensity of the spectral peak of the small molecule substance in the CPMG experimental nuclear magnetic spectrum and the reference H spectrum is used to determine whether the small molecule substance interacts with the target protein. Thus, the screening of small molecules can be completed without the need to invest a large number of staff with professional knowledge.

[0159] In one embodiment of the present application, when the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the nuclear magnetic resonance experiment spectrum acquisition module 601 is specifically used to:

[0160] Obtain the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample;

[0161] The second determination module 604 is specifically configured to:

[0162] When there is a spectral peak at the chemical shift corresponding to the small molecule in the WaterLOGSY experimental spectrum and the spectral peak is reversed by 180 degrees, it is determined that the small molecule interacts with the target protein.

[0163] As can be seen from the above, the small molecule screening method based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the WaterLOGSY experimental spectrum obtained by performing a WaterLOGSY experiment on the sample, determines the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. If the spectral peak corresponding to the small molecule is detected and a 180-degree reversal occurs, it is determined that the small molecule interacts with the target protein. The scheme provided in the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the WaterLOGSY experiment, thereby completing the screening of small molecules without the need for a large number of staff with professional knowledge.

[0164] In one embodiment of the present application, the NMR experimental spectrum acquisition module 601 is specifically used to:

[0165] Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples;

[0166] The nuclear magnetic resonance spectrum data is subjected to preset data processing to obtain a nuclear magnetic resonance experimental spectrum, wherein the preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

[0167] The present application also provides an electronic device, such as Figure 7 As shown, it includes a processor 701 , a communication interface 702 , a memory 703 and a communication bus 704 , wherein the processor 701 , the communication interface 702 , and the memory 703 communicate with each other via the communication bus 704 .

[0168] Memory 703, used for storing computer programs;

[0169] The processor 701 is used to implement the aforementioned small molecule substance screening method based on nuclear magnetic resonance data when executing the program stored in the memory 703.

[0170] As can be seen from the above, the small molecule screening method based on nuclear magnetic resonance data provided in the embodiment of the present application, after obtaining the nuclear magnetic resonance experimental spectrum obtained by performing CPMG experiment or WaterLOGSY experiment on the sample, determines the change of the spectral peak corresponding to the small molecule according to the chemical shift corresponding to the small molecule. For the CPMG experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the intensity change of the spectral peak corresponding to the small molecule. For the WaterLOGSY experiment, the embodiment of the present application judges whether the small molecule interacts with the target protein based on the detection of the spectral peak corresponding to the small molecule and the occurrence of a 180-degree reversal. The scheme provided by the embodiment of the present application can automatically complete the nuclear magnetic resonance data analysis of the CPMG experiment and the WaterLOGSY experiment, thereby completing the screening of small molecules without the need to invest a large number of staff with professional knowledge.

[0171] The communication bus mentioned in the above electronic device can be a Peripheral Component Interconnect (PCI) bus or an Extended Industry Standard Architecture (EISA) bus, etc. The communication bus can be divided into an address bus, a data bus, a control bus, etc. For ease of representation, only one thick line is used in the figure, but it does not mean that there is only one bus or one type of bus.

[0172] The communication interface is used for communication between the above electronic device and other devices.

[0173] The memory may include a random access memory (RAM) or a non-volatile memory (NVM), such as at least one disk memory. Optionally, the memory may also be at least one storage device located away from the aforementioned processor.

[0174] The above-mentioned processor can be a general-purpose processor, including a central processing unit (CPU), a network processor (NP), etc.; it can also be a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components.

[0175] In another embodiment provided in the present application, a computer-readable storage medium is provided, in which a computer program is stored. When the computer program is executed by a processor, the steps of any of the above-mentioned small molecule screening methods based on nuclear magnetic resonance data are implemented.

[0176] In another embodiment provided in the present application, a computer program product comprising instructions is also provided, which, when executed on a computer, enables the computer to execute any of the small molecule screening methods based on nuclear magnetic resonance data in the above embodiments.

[0177] In the above embodiments, it can be implemented in whole or in part by software, hardware, firmware or any combination thereof. When implemented using software, it can be implemented in whole or in part in the form of a computer program product. The computer program product includes one or more computer instructions. When the computer program instructions are loaded and executed on a computer, the process or function described in the embodiment of the present application is generated in whole or in part. The computer may be a general-purpose computer, a special-purpose computer, a computer network, or other programmable device. The computer instructions may be stored in a computer-readable storage medium, or transmitted from one computer-readable storage medium to another computer-readable storage medium. For example, the computer instructions may be transmitted from a website site, a computer, a server or a data center by wired (e.g., coaxial cable, optical fiber, digital subscriber line (DSL)) or wireless (e.g., infrared, wireless, microwave, etc.) mode to another website site, computer, server or data center. The computer-readable storage medium may be any available medium that a computer can access or a data storage device such as a server or a data center that includes one or more available media integrated. The available medium may be a magnetic medium (e.g., a floppy disk, a hard disk, a tape), an optical medium (e.g., a DVD), or a semiconductor medium (e.g., a solid-state drive Solid State Disk (SSD)), etc.

[0178] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0179] Each embodiment in this specification is described in a related manner, and the same or similar parts between the embodiments can be referred to each other, and each embodiment focuses on the differences from other embodiments. In particular, for the device, electronic device, computer-readable storage medium, and computer program product embodiments, since they are basically similar to the method embodiments, the description is relatively simple, and the relevant parts can be referred to the partial description of the method embodiments.

[0180] The above description is only a preferred embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims

1. A method for screening small molecule substances based on nuclear magnetic resonance data, characterized in that: The method comprises: Obtaining a nuclear magnetic resonance spectrum obtained after performing a nuclear magnetic resonance experiment on the sample, wherein the nuclear magnetic resonance experiment is a CPMG experiment or a WaterLOGSY experiment, and the sample contains a target protein and a small molecule substance to be screened; According to the chemical shift corresponding to the small molecule substance, detecting the change of the spectral peak corresponding to the small molecule substance in the nuclear magnetic resonance experimental spectrum; In the case where the NMR experiment is the CPMG experiment, judging whether the small molecule interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule; When the NMR experiment is the WaterLOGSY experiment, whether the small molecule interacts with the target protein is determined based on whether the spectral peak corresponding to the small molecule is reversed by 180 degrees.

2. The method according to claim 1, characterized in that In the case where the NMR experiment is the CPMG experiment, the sample further comprises a calibration substance that does not interact with the target protein, and the step of obtaining a NMR experimental spectrum obtained after performing the NMR experiment on the sample comprises: Obtain a reference H spectrum obtained after performing a nuclear magnetic resonance experiment on the sample; Obtaining a CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample; The step of detecting the change of the spectral peak corresponding to the small molecule substance in the nuclear magnetic resonance experimental spectrum according to the chemical shift corresponding to the small molecule substance comprises: According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental nuclear magnetic resonance spectrum; According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum; Calculating a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak; Calculating a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak; For each first spectrum peak, the intensity decrease ratio corresponding to the first spectrum peak is calculated, wherein the intensity decrease ratio is: the ratio of the decrease amplitude of the second ratio of the target second spectrum peak compared to the first ratio of the first spectrum peak to the second ratio, and the target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak; The step of judging whether the small molecule substance interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule substance comprises: If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substance are greater than a preset ratio, it is determined that the small molecule substance interacts with the target protein.

3. The method according to claim 1, characterized in that In the case where the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the obtaining of the nuclear magnetic resonance spectrum obtained after performing the nuclear magnetic resonance experiment on the sample includes: Obtain the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample; The step of judging whether the small molecule substance interacts with the target protein according to whether the spectrum peak corresponding to the small molecule substance has a 180-degree reversal includes: When there is a spectral peak at the chemical shift corresponding to the small molecule in the WaterLOGSY experimental spectrum and the spectral peak is reversed by 180 degrees, it is determined that the small molecule interacts with the target protein.

4. The method according to claim 1, characterized in that: The obtaining of a nuclear magnetic resonance spectrum obtained after performing a nuclear magnetic resonance experiment on the sample comprises: Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples; The nuclear magnetic resonance spectrum data is subjected to preset data processing to obtain a nuclear magnetic resonance experimental spectrum, wherein the preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

5. A small molecule substance screening device based on nuclear magnetic resonance data, characterized in that: The device comprises: A nuclear magnetic resonance experiment spectrum acquisition module is used to obtain a nuclear magnetic resonance experiment spectrum obtained after performing a nuclear magnetic resonance experiment on a sample, wherein the nuclear magnetic resonance experiment is a CPMG experiment or a WaterLOGSY experiment, and the sample contains a target protein and a small molecule substance to be screened; A peak detection module, used to detect changes in the peaks corresponding to the small molecule in the nuclear magnetic resonance experimental spectrum according to the chemical shift corresponding to the small molecule; A first judgment module is used to judge whether the small molecule substance interacts with the target protein according to the intensity change of the spectrum peak corresponding to the small molecule substance when the nuclear magnetic resonance experiment is the CPMG experiment; The second judgment module is used to judge whether the small molecule substance interacts with the target protein according to whether the spectrum peak corresponding to the small molecule substance undergoes a 180-degree reversal when the nuclear magnetic resonance experiment is the WaterLOGSY experiment.

6. The device according to claim 5, characterized in that In the case where the NMR experiment is the CPMG experiment, the sample further comprises a calibration substance that does not interact with the target protein, and the NMR experiment spectrum acquisition module is specifically used to: Obtain a reference H spectrum obtained after performing a nuclear magnetic resonance experiment on the sample; Obtaining a CPMG experimental NMR spectrum obtained by performing a CPMG relaxation NMR experiment on the sample; The spectrum peak detection module is specifically used for: According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a first spectrum peak corresponding to the small molecule substance and a first standard spectrum peak corresponding to the calibration substance in the CPMG experimental nuclear magnetic resonance spectrum; According to the chemical shifts corresponding to the small molecule substance and the calibration substance, detecting a second spectrum peak corresponding to the small molecule substance and a second standard spectrum peak corresponding to the calibration substance in the reference H spectrum; Calculating a first ratio of the intensity of the first spectrum peak to the intensity of the first standard spectrum peak; Calculating a second ratio of the intensity of the second spectrum peak to the intensity of the second standard spectrum peak; For each first spectrum peak, the intensity decrease ratio corresponding to the first spectrum peak is calculated, wherein the intensity decrease ratio is: the ratio of the decrease amplitude of the second ratio of the target second spectrum peak compared to the first ratio of the first spectrum peak to the second ratio, and the target second spectrum peak is the second spectrum peak with the same chemical shift as the first spectrum peak; The first judgment module is specifically used to: If the intensity decrease ratios of all first spectrum peaks corresponding to the small molecule substance are greater than a preset ratio, it is determined that the small molecule substance interacts with the target protein.

7. The device according to claim 5, characterized in that When the nuclear magnetic resonance experiment is the WaterLOGSY experiment, the nuclear magnetic resonance experiment spectrum acquisition module is specifically used to: Obtain the WaterLOGSY experimental spectrum obtained after performing NMR experiments on the sample; The second judgment module is specifically used to: When there is a spectral peak at the chemical shift corresponding to the small molecule in the WaterLOGSY experimental spectrum and the spectral peak is reversed by 180 degrees, it is determined that the small molecule interacts with the target protein.

8. The device according to claim 5, characterized in that The NMR experimental spectrum acquisition module is specifically used for: Obtaining nuclear magnetic resonance spectrum data obtained after performing nuclear magnetic resonance experiments on samples; The nuclear magnetic resonance spectrum data is subjected to preset data processing to obtain a nuclear magnetic resonance experimental spectrum, wherein the preset data processing includes at least one of the following processing: Fourier transform, phase adjustment, and baseline correction.

9. An electronic device, characterized in that: It includes a processor, a communication interface, a memory and a communication bus, wherein the processor, the communication interface and the memory communicate with each other through the communication bus; Memory, used to store computer programs; A processor, for implementing the method steps described in any one of claims 1 to 4 when executing a program stored in a memory.

10. A computer-readable storage medium, characterized in that: The computer-readable storage medium stores a computer program, and when the computer program is executed by a processor, the method steps described in any one of claims 1 to 4 are implemented.

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