A method for predicting the actual hydrogen bond forming ability of intramolecular hydrogen bonding organic compounds and its application in predicting the partition coefficient between two phases

Abstract

The application provides a prediction method for actual hydrogen bond forming capacity of an organic compound containing intramolecular hydrogen bond and application thereof in prediction of distribution coefficient between two phases, and relates to the technical field of intramolecular hydrogen bond. The actual hydrogen bond forming capacity of the organic compound containing intramolecular hydrogen bond obtained by the prediction method provided in the application can accurately predict various physical and chemical properties such as the distribution coefficient of the compound, without obtaining a large amount of relevant experimental data for the contribution of certain specific groups to the physical and chemical properties and then summarizing, and the method provided in the application has the characteristics of simple operation, simple steps, strong universality, short time consumption, low cost and accurate calculation results of physical and chemical properties such as the distribution coefficient.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of intramolecular hydrogen bond, and particularly relates to a prediction method of actual hydrogen bond forming ability of intramolecular hydrogen bond-containing organic compound and application thereof in prediction of distribution coefficient between two phases. BACKGROUND

[0002] Intramolecular hydrogen bond (IMHB) of organic compound significantly affects their lipophilicity and physical and chemical properties, and it is reported that IMHB can significantly improve the membrane permeability and bioavailability of drugs, thereby improving the success rate of drug research and development, and a drug design strategy based on IMHB has attracted the interest of pharmacologists. It is of great significance to study the quantitative influence of IMHB on the lipophilicity and various physical and chemical properties of organic compounds and drugs.

[0003] Although the influence of IMHB on the physical and chemical properties of organic compounds has been explored by experimental and computational methods, these methods are based on the contribution of certain specific groups to the physical and chemical properties, and a large amount of experimental data is required, and have the disadvantages of complex steps, low accuracy and poor universality. Therefore, it is necessary to develop a simple, universal and accurate method to calculate the influence of IMHB on various physical and chemical properties of compounds. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a prediction method of actual hydrogen bond forming ability of intramolecular hydrogen bond-containing organic compound and application thereof in prediction of distribution coefficient between two phases. The actual hydrogen bond forming ability of intramolecular hydrogen bond-containing organic compound obtained by the prediction method provided by the present application is used to predict various physical and chemical properties of the compound, and the method is simple, has strong universality and the calculation results of physical and chemical properties such as distribution coefficient are accurate.

[0005] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions.

[0006] The present application provides a prediction method of actual hydrogen bond forming ability of intramolecular hydrogen bond-containing organic compound, characterized in that the method comprises the following steps:

[0007] Based on the two-dimensional structure of the intramolecular hydrogen bond-containing organic compound, the hydrogen bond forming ability H of HBD and HBA when no IMHB is formed is obtained HBD and H HBA , and a three-dimensional structure that can form IMHB is generated by a molecular simulation software;

[0008] The H HBD and H HBA are obtained according to formula (1) to obtain ΔG of IMHB HB ;

[0009] The ΔG of IMHB was obtained based on the three-dimensional structure of the organic compound containing intramolecular hydrogen bonds. restr_bond ;

[0010] From the ΔG HB and ΔG restr_bond The ΔG for each IMHB is obtained according to equation (2). IMHB ;

[0011] From the ΔG IMHB K is obtained according to equation (3). IMHB ;

[0012] From the H HBD and K IMHB H is obtained according to equation (4) IM HBD , by the H HBA and K IMHB H is obtained according to equation (5) IM HBA ;

[0013] Wherein, HBD represents hydrogen bond donor, HBA represents hydrogen bond acceptor, and IMHB represents intramolecular hydrogen bond;

[0014] ΔG HB = – (H HBD × H HBA ) / H w Equation (1);

[0015] ΔG IMHB = ΔG HB + ΔG restr_bond Equation (2);

[0016] K IMHB = Equation (3);

[0017] H IM HBD = H HBD / (1+K IMHB Equation (4);

[0018] H IM HBA = H HBA / (1+K IMHB Equation (5);

[0019] Among them, H w The ability of hydrogen atoms or oxygen atoms in water to form hydrogen bonds is 7.02 kJ / mol.

[0020] H HBD This indicates the hydrogen bond forming ability of HBD when IMHB is not formed;

[0021] H HBA represents the hydrogen bond forming ability of HBA when IMHB is not formed;

[0022] ΔG HB represents the free energy change of forming intramolecular hydrogen bond between HBD and HBA in non-polar environment;

[0023] ΔG restr_bond represents the sum of free energy change of inhibiting rotatable bond between HBD and HBA;

[0024] K IMHB represents the equilibrium constant in non-polar environment;

[0025] H IM HBD represents the actual hydrogen bond forming ability of HBD when IMHB is formed;

[0026] H IM HBA represents the actual hydrogen bond forming ability of HBA when IMHB is formed.

[0027] Preferably, the intramolecular hydrogen bond-containing organic compound comprises a compound whose hydrogen bond donor and hydrogen bond acceptor can form hydrogen bond after rotating single bond.

[0028] The present application also provides an application of the prediction method in predicting the physical and chemical properties of the intramolecular hydrogen bond-containing organic compound.

[0029] Preferably, the physical and chemical properties comprise distribution coefficient between two phases or penetration speed in skin.

[0030] Preferably, the two phases comprise water-organic phase, air-organic phase, air-water, air-blood or air-human brain.

[0031] Preferably, the organic phase in the water-organic phase and the air-organic phase independently comprises chloroform, n-octanol or alkane.

[0032] The present application also provides a prediction method of distribution coefficient between two phases of an intramolecular hydrogen bond-containing organic compound, comprising the following steps:

[0033] The prediction method according to the above technical solution obtains H IM HBD and H IM HBA of the intramolecular hydrogen bond-containing organic compound to be tested;

[0034] The prediction method according to the above technical solution obtains H M_HBD , H HBD and HIM HBD According to equation (6), the sum of hydrogen bond forming abilities of all hydrogen bond donors for forming IMHB is obtained. IM M_HBD ;

[0035] H IM M_HBD = H M_HBD + H IM HBD - H HBD Equation (6);

[0036] The sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the tested organic compound containing intramolecular hydrogen bonds that do not form IMHBs (H) M_HBA H HBA and the H IM HBA According to equation (7), the sum of hydrogen bond forming abilities of all hydrogen bond acceptors in the IMHB molecule is H IM M_HBA H IM M_HBD ;

[0037] H IM M_HBA = H M_HBA + H IM HBA - H HBA Equation (7);

[0038] Based on the known H of organic compounds that do not contain intramolecular hydrogen bonds M_HBD H M_HBA and ΔG tr_depol Obtain k1, k2, k3, and c1 of formula (I), and based on k1, k2, k3, c1, and the H of the organic compound containing intramolecular hydrogen bonds to be tested. IM M_HBD H IM M_HBA and ΔG tr_depo The partition coefficient of the organic compound containing intramolecular hydrogen bonds to be tested between the two phases is obtained according to formula (I).

[0039] logP sol =k1×ΔG tr_depol +k2×H M_HBD +k3×H M_HBA +c1 formula (I);

[0040] Among them, P sol The allocation coefficient is logP. sol is the logarithm of the distribution coefficients; k1, k2, k3, and c1 are equation constants;

[0041] The ΔG tr_depol is the free energy change of the compound from the water phase to the non-polar solvent when all atoms in the compound are non-polar atoms.

[0042] Preferably, the organic phase comprises chloroform, n-octanol or alkane.

[0043] The present application also provides a method for predicting the distribution coefficient of an organic compound containing intramolecular hydrogen bond in water-organic phase, comprising the following steps:

[0044] According to the above technical solution, the H IM M_HBD and H IM M_HBA of the organic compound containing intramolecular hydrogen bond to be measured are obtained respectively.

[0045] The S M of the known organic compound containing intramolecular hydrogen bond and the organic compound containing intramolecular hydrogen bond to be measured are calculated respectively. M According to the molecular formula, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i , the S M value of the compound is c+ 0.3h + o + n + 2s + 0.6f + 1.8cl + 2.2br + 2.6i – 0.2Nc3 – 0.6 Nc4; wherein, Nc3 is the number of sp 3 carbon atoms connected to three heavy atoms, and Nc4 is the number of sp 3 carbon atoms connected to four heavy atoms.

[0046] According to the H M_HBD , H M_HBA and S M of the known organic compound not containing intramolecular hydrogen bond, the distribution coefficient of the organic compound containing intramolecular hydrogen bond to be measured in water-organic phase is obtained by multiple linear regression, as shown in formula (II):

[0047] logP sol = k4×S M + k5×H M_HBD + k6×H M_HBA + c2 formula (II);

[0048] wherein, P sol is the distribution coefficient; and logP sollog of the partition coefficient; k4, k5, k6 and c2 are equation constants.

[0049] Preferably, the organic phase in the water-organic phase comprises chloroform, an alkane or n-octanol.

[0050] The actual hydrogen bond forming ability result of the intramolecular hydrogen bond-containing organic compound obtained by the prediction method provided by the present application can accurately predict various physical and chemical properties of the compound, such as the partition coefficient, without obtaining a large amount of relevant experimental data for summarizing the contribution of certain specific groups to the physical and chemical properties. The method provided by the present application has the characteristics of simple operation, simple steps, strong universality, short time consumption, low cost and accurate prediction result of the physical and chemical properties such as the partition coefficient. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 Equilibrium diagram between the compound not forming IMHB (left) and forming IMHB (right);

[0052] Figure 2 Structure diagram of the intramolecular hydrogen bond-containing organic compound in Example 1, wherein HBD: blue hydrogen atom, HBA: red atom. DETAILED DESCRIPTION

[0053] The present application provides a prediction method for the actual hydrogen bond forming ability of an intramolecular hydrogen bond-containing organic compound, comprising the following steps:

[0054] Based on the two-dimensional structure of the intramolecular hydrogen bond-containing organic compound, the hydrogen bond forming ability H of the HBD and HBA when not forming IMHB is obtained HBD and H HBA , and a three-dimensional structure that can form IMHB is generated by molecular simulation software;

[0055] The H HBD and H HBA of the HBD and HBA are obtained according to formula (1) HB ;

[0056] The ΔG of IMHB is obtained according to the three-dimensional structure of the intramolecular hydrogen bond-containing organic compound restr_bond ;

[0057] The ΔG HB and ΔG restr_bond of each IMHB are obtained according to formula (2) IMHB ;

[0058] The K IMHB is obtained according to formula (3) from the ΔG IMHB ;

[0059] The H HBD and KIMHB H is obtained according to formula (4) IM HBD H is obtained according to formula (4) HBA H and K IMHB H is obtained according to formula (5) IM HBA ;

[0060] wherein HBD represents a hydrogen bond donor, HBA represents a hydrogen bond acceptor, and IMHB represents an intramolecular hydrogen bond;

[0061] AG HB = - (H HBD x H HBA ) / H w formula (1);

[0062] AG IMHB = AG HB + AG restr_bond formula (2);

[0063] K IMHB = formula (3);

[0064] H IM HBD = H HBD / (1 + K IMHB ) formula (4);

[0065] H IM HBA = H HBA / (1 + K IMHB ) formula (5);

[0066] wherein H w represents the hydrogen bond forming ability of a hydrogen atom in water or a lone pair of electrons on oxygen, and is 7.02 kJ / mol;

[0067] H HBD represents the hydrogen bond forming ability of a HBD when no IMHB is formed;

[0068] H HBA represents the hydrogen bond forming ability of a HBA when no IMHB is formed;

[0069] AG HB represents the free energy change of formation of an intramolecular hydrogen bond between a HBD and a HBA in a nonpolar environment;

[0070] AG restr_bond represents the sum of the free energy changes of inhibition of rotatable bonds between a HBD and a HBA;

[0071] K IMHB represents the equilibrium constant in a nonpolar environment;

[0072] H IM HBD represents the actual hydrogen bond forming ability of HBD when forming IMHB;

[0073] H IM HBA represents the actual hydrogen bond forming ability of HBA when forming IMHB.

[0074] In the present application, the AG of IMHB is calculated as follows: tr_depol , H HBD and H HBA The calculation of AG is described in detail in the published article: D. Chen, N. Oezguen, P. Urvil, C. Ferguson, S. M. Dann, T. C. Savidge, Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci. Adv. 2, e1501240 (2016).

[0075] In the present application, the molecular simulation software preferably includes SYBYL.

[0076] In the present application, the intramolecular hydrogen bond-containing organic compound preferably includes a compound whose hydrogen bond donor and hydrogen bond acceptor can form a hydrogen bond after rotation of a single bond. In the present application, the intramolecular hydrogen bond-containing organic compound preferably includes any one of the following compounds:

[0077] .

[0078] In the present application, when the distance between the HBD and the HBA is greater than 95% of the sum of the van der Waals radii of the HBD and the HBA, the HBD and the HBA do not form an IMHB; when the distance between the HBD and the HBA is not greater than 95% of the sum of the van der Waals radii of the HBD and the HBA, the HBD and the HBA form an IMHB.

[0079] In the present application, the AG of IMHB is calculated as follows: restr_bond is the sum of the AG of all single bonds between the HBD and the HBA. restr_bond

[0080] In the present application, the H w is 7.02 kJ / mol. In the present application, the AG of one C(sp 3 )-C(sp 3 bond is 3.7 kJ / mol, and the AG of other chemical bonds is 0 kJ / mol. restr_bond restr_bond ​​It will be adjusted according to factors such as the size of the groups on the bond.

[0081] In this invention, the organic compound containing intramolecular hydrogen bonds exists in a balance between HBD and HBA not forming IMHB (left, open form) and forming IMHB (right, closed form), see [reference needed]. Figure 1 When HBD and HBA do not form IMBH (see...) Figure 1 (middle left), their hydrogen bond forming abilities (represented by H) HBD and H HBA (This can be obtained based on the structure of the relevant compound.) When HBD and HBA form IMBH (see...) Figure 1 (middle right) Electron transfer exists between HBD and HBA, resulting in the actual hydrogen bonding ability of HBD and HBA being lower than that of H HBD and H HBA The actual hydrogen bonding capabilities of HBD and HBA are respectively expressed using H IM HBD and H IM HBA Represented by H. IM HBD / H IM HBA With H HBD / H HBA The relationship depends on the equilibrium constant K that forms IMHB. IMHB .

[0082] The prediction method provided by this invention can accurately predict the effect of IMHB on the hydrogen bond forming ability of compounds, thereby achieving accurate prediction of the physicochemical properties of organic compounds containing intramolecular hydrogen bonds. The method is simple, highly versatile, and the calculation results of physicochemical properties such as partition coefficient are accurate.

[0083] This invention also provides the application of the prediction method described above in the physicochemical properties of organic compounds containing intramolecular hydrogen bonds. The actual hydrogen bond forming ability results of organic compounds containing intramolecular hydrogen bonds obtained using the prediction method provided by this invention can accurately predict various physicochemical properties such as the partition coefficient of the compound. This eliminates the need to obtain a large amount of relevant experimental data on the contribution of certain specific groups to the physicochemical properties and then summarize it. The method provided by this invention is characterized by its simple operation, straightforward steps, strong versatility, short processing time, low cost, and accurate calculation results for physicochemical properties such as the partition coefficient.

[0084] In this invention, the physicochemical properties preferably include the partition coefficient of organic compounds containing intramolecular hydrogen bonds between two phases or the penetration rate of organic compounds containing intramolecular hydrogen bonds in the skin.

[0085] In this invention, the two phases preferably include a water-organic phase, an air-organic phase, an air-water phase, an air-blood phase, or an air-brain phase. In this invention, the organic phase in the water-organic phase and the air-organic phase independently preferably includes chloroform, n-octanol, or alkanes; the alkanes preferably include C6-C16 alkanes, more preferably C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, and C16 alkanes, and even more preferably cyclohexane or hexadecane.

[0086] This invention also provides a method for predicting the partition coefficient of organic compounds containing intramolecular hydrogen bonds between two phases, comprising the following steps:

[0087] The prediction method described in the above technical solution is used to obtain the H of the organic compound containing intramolecular hydrogen bonds to be tested. IM HBD and H IM HBA ;

[0088] The sum of the hydrogen bond forming abilities of all hydrogen bond donors of the organic compound containing intramolecular hydrogen bonds to be tested (IMHB) M_HBD H HBD and the H IM HBD According to equation (6), the sum of hydrogen bond forming abilities of all hydrogen bond donors in the molecule forming IMHB is obtained as H. IM M_HBD ;

[0089] H IM M_HBD = H M_HBD + H IM HBD - H HBD Equation (6);

[0090] The sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the organic compound molecule containing intramolecular hydrogen bonds that does not form IMHB (H) M_HBA H HBA and the H IM HBA According to equation (7), the sum of hydrogen bond forming abilities of all hydrogen bond acceptors in the IMHB molecule is H IM M_HBA H IM M_HBD ;

[0091] H IM M_HBA = H M_HBA + H IM HBA - H HBA Equation (7);

[0092] H of the known intramolecular hydrogen bond-free organic compound M_HBD , H M_HBA and ΔG tr_depol obtain k1, k2, k3 and c1 of formula (I) according to k1, k2, k3, c1 and H IM M_HBD , H IM M_HBA and ΔG tr_depo obtain the partition coefficient of the intramolecular hydrogen bond-containing organic compound to be tested between the two phases according to formula (I);

[0093] logP sol = k1 x ΔG tr_depol + k2 x H M_HBD + k3 x H M_HBA + c1 formula (I);

[0094] wherein, P sol is the partition coefficient; logP sol is the logarithm of the partition coefficient; k1, k2, k3 and c1 are equation constants.

[0095] In the present application, the two phases preferably include water-organic phase, air-organic phase, air-water, air-blood or air-human brain. In the present application, the organic phase in the water-organic phase and the air-organic phase independently includes chloroform, n-octanol or alkane; the alkane preferably includes C6~C16 alkane, more preferably includes C6 alkane, C7 alkane, C8 alkane, C9 alkane, C10 alkane, C11 alkane, C12 alkane, C13 alkane, C14 alkane, C15 alkane, C16 alkane, and further preferably is cyclohexane or hexadecane.

[0096] In a specific embodiment of the present application, when the organic phase is hexadecane, the formula (I) is as follows:

[0097] logP 16 = –0.1729 x ΔG tr_depol – 0.1731 x H M_HBD – 0.1748 x H M_HBA + 0.0342.

[0098] In a specific embodiment of the present application, when the organic phase is chloroform, the formula (I) is as follows:

[0099] logP chl = –0.1632 x ΔG tr_depol – 0.1625 x H M_HBD – 0.1016 x H M_HBD+ 0.3220.

[0100] The application further provides a method for predicting the distribution coefficient of an intramolecular hydrogen-bonded organic compound in a water-organic phase, comprising the following steps:

[0101] According to the prediction method, H IM , H M_HBD and S IM of the intramolecular hydrogen-bonded organic compound to be measured are obtained respectively. M_HBA ;

[0102] S M of the intramolecular hydrogen-bonded organic compound to be measured are obtained respectively. M According to the molecular formula, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i , the S M value of the compound is c+ 0.3h + o + n + 2s + 0.6f + 1.8cl + 2.2br + 2.6i – 0.2Nc3 – 0.6 Nc4; wherein, Nc3 is the sp 3 carbon atom number connected with three heavy atoms, and Nc4 is the sp 3 carbon atom number connected with four heavy atoms.

[0103] According to H M_HBD , H M_HBA and S M of the known intramolecular hydrogen-bonded organic compound, the distribution coefficient of the intramolecular hydrogen-bonded organic compound to be measured in the water-organic phase is obtained by multiple linear regression, as shown in formula (II).

[0104] logP sol = k4×S M + k5×H M_HBD + k6×H M_HBA + c2 formula (II).

[0105] Wherein, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k4, k5, k6 and c2 are equation constants.

[0106] In the present application, the organic phase in the water-organic phase preferably comprises chloroform, n-octanol or an alkane; the alkane preferably comprises a C6-C16 alkane, more preferably comprises a C6 alkane, a C7 alkane, a C8 alkane, a C9 alkane, a C10 alkane, a C11 alkane, a C12 alkane, a C13 alkane, a C14 alkane, a C15 alkane, a C16 alkane, and further preferably is cyclohexane or hexadecane.

[0107] The present application is not particularly limited to the known intramolecular hydrogen bond-containing organic compound and the kind and number of the intramolecular hydrogen bond-containing organic compound to be detected, and any intramolecular hydrogen bond-containing organic compound known to those skilled in the art can be used.

[0108] In order to further illustrate the present application, the prediction method of the actual hydrogen bond formation ability of the intramolecular hydrogen bond-containing organic compound provided by the present application and its application, and the prediction method of the distribution coefficient of the intramolecular hydrogen bond-containing organic compound in the aqueous phase and the organic phase will be described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0109] In the following examples, H w is 7.02 kJ / mol. Since the charge reduction between HBD and HBA is caused by the electron transfer between them, it is required that the distance between HBA and HBD is significantly smaller than the sum of their van der Waals radii, ΔG restr_bond is the sum of the free energy changes of inhibiting the rotatable bonds between HBD and HBA, inhibiting one C(sp 3 )-C(sp 3 ) chemical bond. ΔG restr_bond is 3.7 kJ / mol. In the example, ΔG restr_bond of the C-N bond in Ar-NH2 and Ar-NO2 is 0; ΔG restr_bond of the C-O bond in Ar-OH is 2.4 kJ / mol; ΔG restr_bond of the C-O bond in Ar-OCH3 is 0.7 kJ / mol, wherein Ar represents a benzene ring. ΔG tr_depol is the free energy change of the compound from the aqueous phase to the nonpolar solvent, assuming that all atoms in the compound are nonpolar atoms.

[0110] Example 1

[0111] 1. Calculate the hydrogen bond formation ability of the HBD (blue hydrogen atom) and HBA (red atom) forming IMHB in the nine compounds shown in formulas (1)-(5) as follows: Figure 2

[0112] According to the two-dimensional structure of the compound in Figure 2 , obtain the hydrogen bond formation ability H of the HBD and HBA when no IMHB is formed​HBD and H HBA and generate possible three-dimensional structures of the IMHBs by molecular modeling software, from which the H HBD and H HBA The AG of each IMHB is obtained according to formula (1) HB The AG of each IMHB is obtained according to the three-dimensional structure of the compound restr_bond value, from which the AG HB and AG restr_bond The AG of each IMHB is obtained according to formula (2) IMHB from which the AG IMHB K is obtained according to formula (3) IMHB from which the H HBD and K IMHB H is obtained according to formula (4) IM HBD from which the H HBD and K IMHB H is obtained according to formula (5) IM HBA The results are shown in Table 1. The effect of each IMHB on the hydrogen bonding ability of the compound AH IMHB (calculated value) is the difference between (H HBD + H HBA ) and (H IM HBD + H IM HBA ), i.e. AH IMHB= (H HBD + H HBA ) - (H IM HBD + H IM HBA ), and the results are shown in Table 1.

[0113] To show the accuracy of the prediction method provided by the present application, the effect of the IMHBs on the hydrogen bonding ability of the compounds was obtained from the experimental data of the water / hexadecane partition coefficient or water / cyclohexane partition coefficient of the compounds, and the results are expressed by AH IMHB (experimental value). The results show that AH IMHB (calculated value) is very close to AH IMHB (experimental value), and has a good correlation, indicating that the effect of the IMHBs on the hydrogen bonding ability of the compounds can be accurately obtained by the prediction method provided by the present application.

[0114]

[0115] 2. Prediction of the physicochemical properties of IMHB-containing compounds

[0116] 2.1 Calculate the water / hexadecane partition coefficient (logP) of the IMHB-containing compound using equation (8). 16 The model is as follows:

[0117] logP 16 = –0.1729×ΔG tr_depol – 0.1731×H M_HBD – 0.1748×H M_HBA + 0.0342

[0118] N = 166, R 2 = 0.997, SD = 0.155, F = 16439

[0119] Equation (8);

[0120] N is the number of samples; R 2 SD is the square of the correlation coefficient; F is the standard error; H is the statistical statistic. M_HBD and H M_HBA These represent the sum of the hydrogen bond forming abilities of all hydrogen bond donors and all hydrogen bond acceptors in the molecule, respectively.

[0121] Calculate using this model Figure 2 logP of 9 compounds 16 The values ​​and results are shown in Table 2 for logP. 16 The "Count Values ​​(excluding IMHB)" column shows the calculated value compared to the experimental value (logP). 16 The large discrepancy between the "experimental values" column indicates that equation (6) cannot accurately predict the logP of the IMHB compound. 16 .

[0122] Table 2. Effect of the modified hydrogen bonding ability of IMHB based on the present invention on the calculation of logP of IMHB-containing compounds. 16 Improved accuracy

[0123]

[0124] Then, H is calculated using the prediction method provided in this invention. IM M_HBD and H IM M_HBA , using H IM M_HBD and H IM M_HBA H in equation (8) M_HBD and H M_HBA Post-prediction Figure 2 logP of 9 compounds 16 The values ​​and results are shown in Table 2 for logP. 16The calculated value in the "Count Value (Considering IMHB)" column is very close to the experimental value, indicating that the prediction method of this invention can accurately calculate logP of compounds containing IMHB. 16 value.

[0125] 2.2 Using Equation (9) to predict the water / chloroform partition coefficient (logP) without IMHB compounds chl The model is as follows:

[0126] logP chl = –0.1632×ΔG tr_depol – 0.1625×H M_HBD – 0.1016×H M_HBA + 0.3220

[0127] N = 80, R 2 = 0.978, SD = 0.287, F = 563

[0128] Equation (9)

[0129] Calculate using this model Figure 2 logP of 6 compounds chl The values ​​and results are shown in Table 3 for logP. chl The "Count Values ​​(excluding IMHB)" column shows the calculated value compared to the experimental value (logP). chl The "experimental values" column shows a large difference, indicating that equation (9) cannot accurately predict the logP of the IMHB compound. chl .

[0130] Table 3. Effect of the modified hydrogen bonding ability of IMHB based on the present invention on the calculation of logP of IMHB-containing compounds. chl Improved accuracy

[0131]

[0132] Then, H is calculated using the prediction method provided in this invention. IM M_HBD and H IM M_HBA , using H IM M_HBD and H IM M_HBA H in equation (9) M_HBD and H M_HBA Then calculate the logP of these compounds. chl The values ​​and results are shown in Table 3 for logP. chl The calculated value in the "Count Value (Considering IMHB)" column is very close to the experimental value, indicating that the prediction method provided by this invention can accurately calculate the logP of compounds containing IMHB.chl values.

[0133] The above merely describes the preferred embodiments of the present application, and it should be pointed out that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.

Claims

1. A method for predicting the actual hydrogen bond forming ability of an intramolecular hydrogen bonding organic compound, characterized by, The method comprises the steps of: Based on the two-dimensional structure of the intramolecular hydrogen bonding organic compound, the hydrogen bond formation ability H of the HBD and HBA when not forming the IMHB is obtained HBD and H HBA , and a three-dimensional structure that can form the IMHB is generated by molecular simulation software; H HBD and H HBA The AG of IMHB according to formula (1) HB ; ΔG of IMHB is obtained from the three-dimensional structure of the intramolecularly hydrogen-bonded organic compound restr_bond ; ΔG HB and ΔG restr_bond ΔG IMHB of each IMHB is obtained according to formula (2) from the AG IMHB K is obtained from equation (3) IMHB ; from the H HBD and K IMHB H IM HBD from the H HBA and K IMHB H IM HBA ; wherein HBD represents a hydrogen bond donor, HBA represents a hydrogen bond acceptor, and IMHB represents an intramolecular hydrogen bond. AG HB = - (H HBD x H HBA ) / H w Equation (1) AG IMHB = AG HB + AG restr_bond Equation (2) K IMHB = Formula (3); H IM HBD = H HBD / (1+K IMHB Equation (4); H IM HBA = H HBA (1 + K IMHB ) Equation (5); where H w represents the hydrogen bond forming ability of a hydrogen atom in water or a lone pair of electrons on oxygen, is 7.02 kJ / mol; H HBD represents the hydrogen bonding ability of the HBD when no IMHB is formed; H HBA represents the hydrogen bonding ability of HBA when no IMHB is formed; AG HB represents the free energy change of the intramolecular hydrogen bond formation between HBD and HBA in a non-polar environment; AG restr_bond represents the sum of the free energy changes that inhibit the rotatable bonds between HBD and HBA; K IMHB represents the equilibrium constant in non-polar environment; H IM HBD represents the actual hydrogen bond forming ability of the HBD when forming an IMHB; H IM HBA represents the actual hydrogen bond forming ability of the HBA when forming an IMHB.

2. The prediction method of claim 1, wherein, The intramolecular hydrogen bond-containing organic compound includes a compound whose hydrogen bond donor and hydrogen bond acceptor can form a hydrogen bond by rotating a single bond.

3. The prediction method according to claim 1 or 2, characterized in that, The prediction method is used to predict a physicochemical property of the intramolecular hydrogen bond-containing organic compound.

4. The prediction method of claim 3, wherein, The physicochemical property includes a distribution coefficient between two phases or a penetration speed in a skin.

5. The prediction method of claim 4, wherein, The two phases include a water-organic phase, an air-organic phase, air-water, air-blood, or air-human brain.

6. The prediction method of claim 4, wherein, The organic phase in the water-organic phase and the air-organic phase independently includes chloroform, n-octanol, or an alkane.

7. A method for predicting the partition coefficient between two phases of an intramolecularly hydrogen-bonded organic compound, characterized by, The method comprises the steps of: The prediction method according to any one of claims 1-2 obtains H IM HBD and H IM HBA ; H is the sum of the hydrogen bond forming ability of all hydrogen bond donors of the molecule of the organic compound under test not forming IMHB M_HBD , H HBD and the sum H IM HBD H is the sum of the hydrogen bond forming ability of all hydrogen bond donors of the molecule of the organic compound under test not forming IMHB IM M_HBD ; H IM M_HBD = H M_HBD + H IM HBD - H HBD Equation (6); H, the sum of hydrogen bond forming ability of all hydrogen bond acceptors not forming IMHB by the molecule of the organic compound to be measured containing intramolecular hydrogen bond M_HBA , H HBA and the H IM HBA , the sum of hydrogen bond forming ability of all hydrogen bond acceptors of the molecule forming IMHB is respectively H IM M_HBA , H IM M_HBD ; H IM M_HBA = H M_HBA + H IM HBA - H HBA Equation (7); H of the known intramolecular hydrogen bond-free organic compound M_HBD , H M_HBA and ΔG tr_depol k1, k2, k3 and c1 of formula (I) are obtained from H IM M_HBD , H IM M_HBA and ΔG tr_depo the partition coefficient of the intramolecular hydrogen bond-containing organic compound to be tested between the two phases is obtained from formula (I); logP sol = k1 x AG tr_depol + k2 x H M_HBD + k3 x H M_HBA + c1 Equation (I); where P sol is the partition coefficient; logP sol is the logarithm of the partition coefficient; k1, k2, k3, and c1 are equation constants; the AG tr_depol is the free energy change of the compound from water to a non-polar solvent assuming all atoms in the compound are non-polar atoms.

8. The prediction method of claim 7, wherein, The organic phase includes chloroform, n-octanol, or an alkane.

9. A method for predicting the partition coefficient of an intramolecularly hydrogen-bonded organic compound in a water-organic phase, characterized by, The method comprises the steps of: The prediction method according to any one of claims 1-2, respectively, obtains H IM M_HBD and H IM M_HBA ; S M of the known intramolecular hydrogen bond-containing organic compound and the to-be-detected intramolecular hydrogen bond-containing organic compound are calculated respectively M According to the calculation of the molecular formula, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i , the S M value of the compound is c + 0.3h + o + n + 2s + 0.6f + 1.8cl + 2.2br + 2.6i – 0.2Nc3 – 0.6 Nc4; wherein, Nc3 is the number of sp 3 carbon atoms connected with three heavy atoms, and Nc4 is the number of sp 3 carbon atoms connected with four heavy atoms. According to the H of the known intramolecular hydrogen bond-free organic compound M_HBD , H M_HBA , S M , the partition coefficient of the intramolecular hydrogen bond-containing organic compound to be measured in water-organic phase represented by formula (II) is obtained by multiple linear regression. logP sol = k4 x S M + k5 x H M_HBD + k6 x H M_HBA + c2 Equation (II); where P sol is the partition coefficient; logP sol is the logarithm of the partition coefficient; k4, k5, k6, and c2 are equation constants.

10. The prediction method of claim 9, wherein, The organic phase in the water-organic phase includes chloroform, an alkane, or n-octanol.

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