CN109493923B - Method for calculating partition constant of compound in water and any solvent - Google Patents

Abstract

The invention provides two methods for calculating a distribution constant of a compound in water and any solvent, belonging to the field of computational chemistry. The invention establishes two alternative logPs_octTo more accurately predict the properties of the compounds of formula I and formula II. The model can be suitable for different environments and unknown environments, and can accurately calculate the free energy change of the compound transferred from water to any solvent, so that the distribution constant of the compound transferred from water to any solvent can be accurately calculated. The model is expected to be capable of replacing logP_octTo more accurately predict the physicochemical and pharmacokinetic properties of the compound. The results of the examples show that the calculated values obtained by the method provided by the application are very close to the actual values, which indicates that the distribution constants can be accurately calculated by the method provided by the invention.

Description

Method for calculating partition constant of compound in water and any solvent

Technical Field

The invention relates to the technical field of computational chemistry, in particular to a method for calculating a partition constant of a compound in water and any solvent.

Background

Drug development has an important role in improving the physical health of humans and promoting economic development, but new drug development is a time-consuming and costly process, one of the main reasons being that about 90% of drug candidates are rejected during clinical period due to unsatisfactory Absorption, Distribution, Metabolism, excretion and toxicity (Absorption, Distribution, Metabolism, excretion: ADMET). The research and development strategy of the new drug is changed from the traditional screening mode taking activity as the leading factor to the parallel evaluation of the ADMET property of the compound while determining the drug effect, the prediction of the ADMET property of the drug becomes an important link of the early-stage research and development of the drug, and the accurate prediction of the ADMET property is a necessary condition for improving the research and development success rate of the drug and reducing the development time and cost.

Pharmaceutical chemists have proposed some predictive drugs ADMEModels of T performance, such as Caco-2 cell permeability models to predict drug absorption, Blood Brain Barrier (BBB) models to predict drug distribution in vivo, and the like. All models can not be separated from logP_octThis is a parameter important for lipophilicity. However, because the environment in the biological system is greatly different from that of n-octanol and the environment in the biological system corresponding to different ADMET performances is also greatly different, logP cannot be determined_octOr any other single partition constant to accurately predict various physicochemical and pharmacokinetic properties of the compound. By logP_octEmpirical rules and models established on the basis cannot accurately predict the performance of the ADMET drug in many cases and can cause misleading, and many medicinal chemists have suspected logP_octTo measure the accuracy of the lipophilicity of the drug.

Disclosure of Invention

The object of the present invention is to provide a method for calculating the partition constant of a compound in water and any solvent, which can be used for calculating the partition constant of a compound between water and any solvent, for replacing logP_octAnd the accuracy of predicting various physicochemical properties and pharmacokinetic properties of the compound is increased.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a method for calculating the partition constant of a compound in water and any solvent, comprising the following steps:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating the deltaG of all the compounds according to the chemical structural formulas of the known compound and the compound to be tested^alk _{tr_depol}、H_HBDAnd H_HBA；

(3) logP of known compound_sol、ΔG^alk _{tr_depol}、H_HBDAnd H_HBACalculated by substituting in formula IOut of corresponding k₁、k₂、k₃And c₁(ii) a Δ G of the test Compound^alk _{tr_depol}、H_HBD、H_HBAAnd k is obtained₁、k₂、k₃And c₁Calculated logP in formula I_solConverted to obtain P_sol；

logP_sol＝k₁*ΔG^alk _{tr_depol}+k₂*H_HBD+k₃*H_HBA+c₁Formula I

In the formula I, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₁、k₂、k₃and c₁Is an equation constant;

ΔG^alk _{tr_depol}、H_HBDand H_HBAAs a compound parameter,. DELTA.G^alk _{tr_depol}Is the free energy change of the non-polar compound from the aqueous phase into the non-polar solvent, assuming all atoms in the compound are non-polar; h_HBDIs the sum of the hydrogen bond forming abilities of all hydrogen bond donors of the compound; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

The present invention also provides another method of calculating the partition constant of a compound in water and any solvent, comprising the steps of:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating SASA and H of all compounds according to chemical structural formulas of known compounds and compounds to be detected_HBDAnd H_HBA；

(3) logP of known compound_sol、SASA、H_HBDAnd H_HBACalculating corresponding k in formula II₄、k₅、k₆And c₂(ii) a SASA, H of the test compound_HBD、H_HBAAnd k is obtained₄、k₅、k₆And c₂Calculated logP in formula II_solConverted to obtain P_sol；

logP_sol＝k₄*SASA+k₅*H_HBD+k₆*H_HBA+c₂Formula II

In the formula II, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₄、k₅、k₆and c₂Is an equation constant;

SASA、H_HBDand H_HBAAs a compound parameter, SASA is the solvent accessible surface area of the compound; h_HBDIs the sum of the hydrogen bond forming abilities of all hydrogen bond donors of the compound; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

The present invention provides two methods of calculating the partition constant of a compound in water and any solvent. The invention establishes two alternative logPs_octTo more accurately predict the properties of the compounds of formula I and formula II. The model can be suitable for different environments and unknown environments, and can accurately calculate the free energy change of the compound transferred from water to any solvent, so that the distribution constant of the compound transferred from water to any solvent can be accurately calculated. The model is expected to be capable of replacing logP_octTo more accurately predict the physicochemical and pharmacokinetic properties of the compound. The results of the examples show that the calculated values obtained by the method provided by the application are very close to the actual values, which indicates that the distribution constants can be accurately calculated by the method provided by the invention.

Drawings

FIG. 1 is a schematic diagram of a thermodynamic cycle deriving the change in free energy of a compound transferred from water to any solvent;

FIG. 2 is H^oct _HBAAnd H_HBAThe linear relationship of (a);

FIG. 3 shows Δ G in hexadecane as solvent^alk _{tr_depol}And linearity of SASAA relationship;

FIG. 4 shows n-octanol solvent Δ G^alk _{tr_depol}And linear relationship of SASA;

FIG. 5 shows the calculated value [ logP ] of example 1_oct(calc)]And the experimental value [ logP_oct(obsv)]A relationship diagram of (1);

FIG. 6 shows the calculated value [ logP ] of example 2_chl(calc)]And the experimental value [ logP_chl(obsv)]A graph of the relationship (c).

FIG. 7 shows the calculated value [ logP ] of example 3₁₆(calc)]And the experimental value [ logP₁₆(obsv)]A graph of the relationship (c).

FIG. 8 shows the calculated value [ logP ] of example 4_chl(calc)]And the experimental value [ logP_chl(obsv)]A graph of the relationship (c).

Detailed Description

The invention provides a method for calculating the partition constant of a compound in water and any solvent, comprising the following steps:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating the deltaG of all the compounds according to the chemical structural formulas of the known compound and the compound to be tested^alk _{tr_depol}、H_HBDAnd H_HBA；

(3) logP of known compound_sol、ΔG^alk _{tr_depol}、H_HBDAnd H_HBACalculating corresponding k in formula I₁、k₂、k₃And c₁(ii) a Δ G of the test Compound^alk _{tr_depol}、H_HBD、H_HBAAnd k is obtained₁、k₂、k₃And c₁Calculated logP in formula I_solConverted to obtain P_sol；

logP_sol＝k₁*ΔG^alk _{tr_depol}+k₂*H_HBD+k₃*H_HBA+c₁Formula I

In the formula I, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₁、k₂、k₃and c₁Is an equation constant;

ΔG^alk _{tr_depol}、H_HBDand H_HBAAs a compound parameter,. DELTA.G^alk _{tr_depol}Is the free energy change of the non-polar compound from the aqueous phase into the non-polar solvent, assuming all atoms in the compound are non-polar; h_HBDIs the sum of the hydrogen bond forming abilities of all hydrogen bond donors of the compound; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

The invention provides at least 9 known compounds whose logP in the solvent to be tested_solAnd chemical structural formulae are known. The known compound provided by the invention specifically refers to logP in a solvent to be tested_solAnd compounds of known chemical formula; the number of said known compounds is at least 9, in principle the greater the better, the greater the number of known compounds the higher the accuracy of the calculation; the known compound may be any compound, and there is no particular requirement for its specific selection.

The invention provides at least 1 test compound, the chemical structural formula of which is known, and logP in a test solvent_solUnknown; the test compound may be any kind of compound, and there is no particular requirement for its specific selection.

The invention calculates the delta G of all the compounds according to the chemical structural formulas of the known compound and the compound to be tested^alk _{tr_depol}、H_HBDAnd H_HBA. In the present invention, the Δ G^alk _{tr_depol}、H_HBDAnd H_HBAAs a compound parameter,. DELTA.G^alk _{tr_depol}Is the free energy change of the non-polar compound from the aqueous phase into the non-polar solvent, assuming all atoms in the compound are non-polar; h_HBDCapability of hydrogen bond formation of all hydrogen bond donors of compoundAnd; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound. Δ G of the invention^alk _{tr_depol}、H_HBDAnd H_HBASee the published article for details of the calculation method definition and calculation: chen, n.oezguen, p.urvil, c.ferguson, s.m.dann, t.c.savidge, Regulation of protein-ligand binding affinity by hydrogen binding pair. sci.adv.2, e1501240 (2016).

The invention relates to the logP of the known compound_sol、ΔG^alk _{tr_depol}、H_HBDAnd H_HBASubstituting the formula I to obtain the corresponding k by calculation according to a multiple linear regression method₁、k₂、k₃And c₁(ii) a Δ G of the test Compound^alk _{tr_depol}、H_HBD、H_HBAAnd k is obtained₁、k₂、k₃And c₁Calculated logP in formula I_solConverted to obtain P_sol. In the present invention, k is₁、k₂、k₃And c₁And the kind of the solvent, regardless of the kind of the compound.

In the present invention, the formula I is obtained by the thermodynamic cycle shown in FIG. 1, and all Δ G in FIG. 1 represent the change in free energy due to the change in noncovalent interaction. RX represents a small organic or pharmaceutical molecule, wherein R represents a non-polar atom or group, X in dark grey represents a polar atom or group, X in light grey represents a non-polar atom or group, water represents water as a solvent, and solvent represents any solvent. The thermodynamic cycle is a calculation of the free energy change (Δ G) of the transfer of compound RX from aqueous solution to any solution_{tr_M}). From this thermodynamic cycle, the following are obtained: Δ G_{tr_M}Equivalent to the free energy change (Δ G) of the transfer of nonpolar RX from aqueous solution to any solution_{tr_depolM}) Plus the difference (AG) between the change in free energy associated with non-donation by depolarizing polar RX in aqueous and in any solution^wat _depol–ΔG^solv _depol)：

ΔG_{tr_M}＝ΔG_{tr_depolM}+(ΔG^wat _depol–ΔG^solv _depol) And (3) formula III.

In formula III,. DELTA.G^wat _depolAnd Δ G^solv _depolRespectively RX depolarizes in aqueous solution and in any solution to cause a change in free energy associated with non-donating effects; Δ G^wat _depol–ΔG^solv _depolIs a free energy change transferred from an aqueous solution to an arbitrary solution due to the electrostatic action of X. If the transfer is from an aqueous solution to a nonpolar solvent,. DELTA.G^wat _depol–ΔG^solv _depolIs hydrogen bond forming ability, Δ G of one molecule^wat _depol–ΔG^solv _depolThat is the hydrogen bond forming ability (H) of the molecule_M) Δ G of hydrogen bond acceptor in one molecule^wat _depol–ΔG^solv _depolThat is, the hydrogen bond forming ability (H) of its hydrogen bond acceptor_HBA) Δ G of hydrogen bond donor in one molecule^wat _depol–ΔG^solv _depolThat is, the hydrogen bond-forming ability (H) of its hydrogen bond donor_HBD). Δ G of molecules, hydrogen bond acceptors and hydrogen bond donors if transferred from aqueous solution to n-octanol solvent^wat _depol–ΔG^solv _depolRespectively with H^oct _M、H^oct _HBAAnd H^oct _HBDAnd (4) showing.

As shown in FIG. 2, H^oct _HBAAnd H_HBAIn direct proportion, likewise, for any solvent H^solv _HBAAnd H_HBAIs in direct proportion. Therefore, Δ G in formula III due to electrostatic interaction of hydrogen bond acceptor^wat _depol–ΔG^solv _depolAnd H_HBAProportional ratio (k)₂*H_HBD). Similarly, Δ G in formula III due to electrostatic interaction of hydrogen bond donor^wat _depol–ΔG^solv _depolAnd H_HBDProportional ratio (k)₃*H_HBA)。

This pattern iii becomes the following equation:

ΔG_{tr_M}＝k₁*ΔG^alk _{tr_depol}+k₂*H_HBD+k₃*H_HBAformula IV

Due to errors in the calculation and experimental data, a constant c is added after the formula IV₁. Due to logP_sol＝ΔG_{tr_M}(2.303. multidot. R. multidot. T), where R is a rational gas constant and T is temperature, so that at normal temperature, formula IV becomes formula I.

The present invention also provides another method for calculating the partition constant of a compound in water and any solvent, comprising the steps of:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating SASA and H of all compounds according to chemical structural formulas of known compounds and compounds to be detected_HBDAnd H_HBA；

(3) logP of known compound_sol、SASA、H_HBDAnd H_HBACalculating corresponding k in formula II₄、k₅、k₆And c₂(ii) a SASA, H of the test compound_HBD、H_HBAAnd k is obtained₄、k₅、k₆And c₂Calculated logP in formula II_solConverted to obtain P_sol；

logP_sol＝k₄*SASA+k₅*H_HBD+k₆*H_HBA+c₂Formula II

In the formula II, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₄、k₅、k₆and c₂Is an equation constant;

SASA、H_HBDand H_HBAAs a compound parameter, SASA is the solvent accessible surface area of the compound; h_HBDHydrogen bonds which are all hydrogen bond donors of the compoundSum of forming ability; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

The step (1) of the method is consistent with the requirement of the step (1) of the method, and the detailed description is omitted.

Said method H_HBDAnd H_HBAThe method is consistent with the requirements of the method, and the detailed description is omitted.

The SASA in the present methods is the solvent accessible surface area of the compound. In the present invention, the Δ G^alk _{tr_depol}Is obtained by SASA, and Δ G^alk _{tr_depol}There is a good correlation with the SASA, and the relationship is shown in FIG. 3. As shown in FIG. 4, the results of the examination using n-octanol solvent as an example show that the nonpolar compound is transferred from the aqueous solution to Δ G in the n-octanol solvent_{tr_depolM}Proportional to the compound's SASA.

The invention relates to the logP of the known compound_sol、SASA、H_HBDAnd H_HBACalculating corresponding k in formula II₄、k₅、k₆And c₂(ii) a SASA, H of the test compound_HBD、H_HBAAnd k is obtained₄、k₅、k₆And c₂Calculated logP in formula II_solConverted to obtain P_sol。

The two methods of calculating the partition constants of a compound in water and any solvent provided by the present invention can be used to calculate the partition constants for any type and any number of solvents.

The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.

Example 1

Water/n-octanol partition constant (logP)_oct) The calculation of (2):

we used 242 cells with logP_octThe compounds of value are used to model the constant k₁，k₂，k₃And c₁Using 245 molecules with logP_octCompounds of value used to verify model accuracyAnd (4) sex.

With 242 cells having logP_octΔ G of value Compound^alk _{tr_depol}，H_HBD，H_HBAAnd logP_octThe model established by the method of multiple linear regression for data is as follows:

logP_oct＝0.1482*ΔG^alk _{tr_depol}+0.00385*H_HBD–0.1188*H_HBA+0.1159 (1)

N＝242,R²＝0.985,stdev＝0.234。

formula (1) was used to calculate the logP of 245 compounds_octValue, calculated value [ logP_oct(calc)]And the experimental value [ logP_oct(obsv)]The relationship of (2) is shown in FIG. 5. As can be seen from fig. 5, the calculated values and the actual values are sufficiently close to indicate that the dispensing constant can be accurately calculated using the method of the present invention.

Example 2

Water/chloroform partition constant (logP)_chl) The calculation of (2):

with 80 having logP_chlValue of the compound was modeled using 75 compounds with logP_chlCompound validation model of values.

With 80 having logP_chlΔ G of value Compound^alk _{tr_depol}，H_HBD，H_HBAAnd logP_chlThe model established by the method of multiple linear regression for data is as follows:

logP_chl＝0.1632*ΔG^alk _{tr_depol}–0.1625*H_HBD–0.1016*H_HBA+0.3220 (2)

N＝80,R²＝0.978,stdev＝0.287.

the formula (2) was used to calculate the logP of 75 compounds_chlValue, calculated value [ logP_chl(calc)]And the experimental value [ logP_chl(obsv)]The relationship of (2) is shown in FIG. 6. As can be seen from fig. 6, the calculated values and actual values are sufficiently close to indicate that the dispensing constant can be accurately calculated using the method of the present invention.

Example 3

Water/n-hexadecane partition constant (logP)₁₆) The calculation of (2):

with 166 cells having logP₁₆Modeling of the values with 160 compounds having logP₁₆Compound validation model of values.

With 166 cells having logP₁₆Δ G of value Compound^alk _{tr_depol}，H_HBD，H_HBAAnd logP₁₆The model established by the method of multiple linear regression for data is as follows:

logP₁₆＝0.1729*ΔG^alk _{tr_depol}–0.1731*H_HBD–0.1748*H_HBA+0.0342 (3)

N＝166,R²＝0.997,stdev＝0.155.

formula (3) was used to calculate the logP of 160 compounds₁₆Value, calculated value [ logP₁₆(calc)]And the experimental value [ logP₁₆(obsv)]The relationship of (2) is shown in FIG. 7. As can be seen from FIG. 7, the calculated value and the actual value are very close, using the parameter Δ G^alk _{tr_depol}，H_HBDAnd H_HBAThe water/n-hexadecane partition constant of a compound can be accurately predicted by the structure of the compound.

Example 4

Calculation of Water/chloroform partition constant (logP) based on formula II_chl)：

With 80 having logP_chlValue of the compound was modeled using 75 compounds with logP_chlCompound validation model of values.

With 80 having logP_chlSASA, H of a compound of value_HBD，H_HBAAnd logP_chlThe model established by the method of multiple linear regression for data is as follows:

logP_chl＝0.02925*SASA–0.1530*H_HBD–0.1048*H_HBA-0.0175 (4)

N＝80,R²＝0.976,stdev＝0.309.

formula (4) was used to calculate logP for 75 compounds_chlValue, calculated value [ logP_chl(calc)]And the experimental value [ logP_chl(obsv)]The relationship of (2) is shown in FIG. 8. As can be seen from FIG. 8, the calculated and actual values are sufficiently close that the method of the present invention can be used toThe dispensing constant is accurately calculated.

TABLE 1 examples 1-4 related experimental data and results data

Δ G in Table 1_depol,H_HBD,H_HBA,H_MAnd

the units of (a) are all kJ/mol; the unit of SASA is

&: calculation based on the SASA resume model. *: means that the compounds have intramolecular hydrogen bonds, and that these contain H of the intramolecular hydrogen bond compound_HBDAnd H_HBAThe values cannot be found by article: chen, n.oezguen, p.urvil, c.ferguson, s.m.dann, t.c.savidge, Regulation of protein-ligand binding affinity by hydrogen binding pair. sci.adv.2, e1501240(2016) of these compounds, but by the method of log p of these compounds₁₆And logP_octThe experimental data of (2) are calculated. H of these compounds_HBDSee the published article for details of the calculation methods of (c): chen, d.; li, Y.; zhao, m.; tan, w.; li, X.; savidge, t.; guo, w.; fan, X.efficient lead optimization targeting the display of branched receiver-like molecules. Phys. chem. Phys.2018,20,24399-_HBAThe value is their H_MValue minus H_HBA。

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (2)

1. A method of calculating the partition constant of a compound in water and any solvent, comprising the steps of:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating the deltaG of all the compounds according to the chemical structural formulas of the known compound and the compound to be tested^alk _{tr_depol}、H_HBDAnd H_HBA；

(3) logP of known compound_sol、ΔG^alk _{tr_depol}、H_HBDAnd H_HBACalculating corresponding k in formula I₁、k₂、k₃And c₁(ii) a Δ G of the test Compound^alk _{tr_depol}、H_HBD、H_HBAAnd k is obtained₁、k₂、k₃And c₁Calculated logP in formula I_solConverted to obtain P_sol；

logP_sol＝k₁*ΔG^alk _{tr_depol}+k₂*H_HBD+k₃*H_HBA+c₁Formula I

In the formula I, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₁、k₂、k₃and c₁Is an equation constant;

ΔG^alk _{tr_depol}、H_HBDand H_HBAAs a compound parameter,. DELTA.G^alk _{tr_depol}Is the free energy change of the non-polar compound from the aqueous phase into the non-polar solvent, assuming all atoms in the compound are non-polar; h_HBDIs the sum of the hydrogen bond forming abilities of all hydrogen bond donors of the compound; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

2. A method of calculating the partition constant of a compound in water and any solvent, comprising the steps of:

(1) providing at least 9 known compounds having logP in the solvent to be tested_solAnd the chemical structural formula is known;

providing at least 1 test compound, the chemical structure of which is known;

(2) calculating SASA and H of all compounds according to chemical structural formulas of known compounds and compounds to be detected_HBDAnd H_HBA；

(3) logP of known compound_sol、SASA、H_HBDAnd H_HBACalculating corresponding k in formula II₄、k₅、k₆And c₂(ii) a SASA, H of the test compound_HBD、H_HBAAnd k is obtained₄、k₅、k₆And c₂Calculated logP in formula II_solConverted to obtain P_sol；

logP_sol＝k₄*SASA+k₅*H_HBD+k₆*H_HBA+c₂Formula II

In the formula II, P_solTo assign constants, logP_solIs the logarithm of the allocation constant;

k₄、k₅、k₆and c₂Is an equation constant;

SASA、H_HBDand H_HBAAs a compound parameter, SASA is the solvent accessible surface area of the compound; h_HBDIs the sum of the hydrogen bond forming abilities of all hydrogen bond donors of the compound; h_HBAIs the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the compound.

Images