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Method for Calculating Partition Constants of Compounds in Water and Arbitrary Solvents

A technology for assigning constants and compounds, applied in the field of computational chemistry, can solve problems such as inability to accurately predict the physical and chemical properties of compounds, inability to accurately predict the ADMET performance of drugs, and misleading

Active Publication Date: 2021-07-30
GANNAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because the environment in the biological system is quite different from that of n-octanol, and the environment in the biological system corresponding to different ADMET properties is also quite different, therefore, it cannot be determined by logP oct or any other single partition constant to accurately predict various physicochemical and pharmacokinetic properties of compounds
in logP oct Empirical rules and models based on ADMET cannot accurately predict drug ADMET performance in many cases, and can be misleading. Many medicinal chemists have suspected that the use of logP oct To measure the accuracy of drug lipophilicity

Method used

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  • Method for Calculating Partition Constants of Compounds in Water and Arbitrary Solvents
  • Method for Calculating Partition Constants of Compounds in Water and Arbitrary Solvents
  • Method for Calculating Partition Constants of Compounds in Water and Arbitrary Solvents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Water / n-octanol partition constant (logP oct ) calculation:

[0070] We use 242 with logP oct Compounds with values ​​are used to build the model to obtain the constant k 1 , k 2 , k 3 and c 1 , with 245 logP oct Compounds with values ​​were used to verify the accuracy of the model.

[0071] with 242 logP oct The value of the compound's ΔG alk tr_depol , H HBD , H HBA and logP oct The model established by the method of multiple linear regression for the data is:

[0072] logP oct =0.1482*ΔG alk tr_depol +0.00385*H HBD –0.1188*H HBA +0.1159 (1)

[0073] N=242,R 2 = 0.985, stdev = 0.234.

[0074] Formula (1) was used to calculate the logP of 245 compounds oct value, its calculated value [logP oct (calc)] and experimental value [logP oct (obsv)] The relationship is as Figure 5 shown. Depend on Figure 5 It can be seen that the calculated value is very close to the actual value, indicating that the method of the present invention can be used to ac...

Embodiment 2

[0076] Water / chloroform partition constant (logP chl ) calculation:

[0077] with a logP of 80 chl Compounds of value are modeled using 75 with logP chl Compound validation model for values.

[0078] with a logP of 80 chl The value of the compound's ΔG alk tr_depol , H HBD , H HBA and logP chl The model established by the method of multiple linear regression for the data is:

[0079] logP chl =0.1632*ΔG alk tr_depol –0.1625*H HBD –0.1016*H HBA +0.3220 (2)

[0080] N=80,R 2 = 0.978, stdev = 0.287.

[0081] Formula (2) was used to calculate the logP of 75 compounds chl value, its calculated value [logP chl (calc)] and experimental value [logP chl (obsv)] The relationship is as Figure 6 shown. Depend on Figure 6 It can be seen that the calculated value is very close to the actual value, indicating that the method of the present invention can be used to accurately calculate the distribution constant.

Embodiment 3

[0083] Water / n-hexadecane partition constant (logP 16 ) calculation:

[0084] with 166 logP 16 Compounds of value are modeled with 160 logP 16 Compound validation model for values.

[0085] with 166 logP 16 The value of the compound's ΔG alk tr_depol , H HBD , H HBA and logP 16 The model established by the method of multiple linear regression for the data is:

[0086] logP 16 =0.1729*ΔG alk tr_depol –0.1731*H HBD –0.1748*H HBA +0.0342 (3)

[0087] N=166,R 2 = 0.997, stdev = 0.155.

[0088] Formula (3) was used to calculate the logP of 160 compounds 16 value, its calculated value [logP 16 (calc)] and experimental value [logP 16 (obsv)] The relationship is as Figure 7 shown. Depend on Figure 7 It can be seen that the calculated value is very close to the actual value, and the parameter ΔG alk tr_depol , H HBD and H HBA The water / n-hexadecane partition constant of a compound can be accurately predicted from its structure.

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Abstract

The invention provides two methods for calculating the distribution constant of compounds in water and any solvent, and belongs to the field of computational chemistry. The present invention establishes two alternative logP oct Models to more accurately predict the properties of compounds—Formula I and Formula II. The model can be applied to various environments and unknown environments, and can accurately calculate the free energy change of the compound transferred from water to any solvent, so that it can accurately calculate the partition constant of the compound transferred from water to any solvent. This model is expected to be able to replace logP oct To more accurately predict the physicochemical properties and pharmacokinetic properties of compounds. From the results of the examples, it can be seen that the calculated value obtained by the method provided in the present application is very close to the actual value, indicating that the method of the present invention can be used to accurately calculate the distribution constant.

Description

technical field [0001] The invention relates to the technical field of computational chemistry, in particular to a method for calculating the distribution constant of compounds in water and any solvent. Background technique [0002] Drug research and development plays an important role in improving human health and promoting economic development, but new drug research and development is a time-consuming and cost-intensive process, one of the main reasons is that about 90% of candidate drugs are due to absorption, distribution, metabolism, Excretion and toxicity (Absorption, Distribution, Metabolism, Excretion and Toxicity: ADMET) and other performance are not ideal and were eliminated. The new drug development strategy has changed from the traditional activity-oriented screening mode to parallel evaluation of the ADMET properties of compounds while measuring drug efficacy. Predicting the ADMET properties of drugs has become an important part of the early drug development. Ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G16C20/30G16C20/10
Inventor 陈德良范小林李勋李亿保
Owner GANNAN NORMAL UNIV
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