Molecule acid and alkaline dissociation constant prediction method based on layered atomic addition model

A technology of dissociation constant and prediction method, which is applied in the direction of testing pharmaceutical preparations, electrical digital data processing, special data processing applications, etc., and can solve problems such as low bioavailability, high cost, and poor absorption

Inactive Publication Date: 2009-04-29
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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Problems solved by technology

Approximately 90% of drug candidates are eliminated during the clinical phase, which is a major factor in the expensive R&D process
A large par

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  • Molecule acid and alkaline dissociation constant prediction method based on layered atomic addition model
  • Molecule acid and alkaline dissociation constant prediction method based on layered atomic addition model
  • Molecule acid and alkaline dissociation constant prediction method based on layered atomic addition model

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Embodiment 1

[0046] Embodiment 1. Parameter table construction

[0047] The least squares method is the most commonly used method for fitting the compositional parameters of the traditional group / atom summation model, but for nonlinear models, the least squares method is not suitable for modeling. Adaptive optimization has been proven to be an effective method for dealing with problems without knowledge of the search space (solution space). In this study, the inventors used the genetic algorithm for adaptive parameter estimation, and the specific steps are as follows:

[0048] Data samples are from Lange's Handbook of Chemistry. As a sampling standard, select the pK measured in aqueous solution at 25°C a The experimental values ​​totaled 1300 compounds, covering a wide space of chemical diversity. Among them, the most common 41 kinds of dissociation centers are selected, and their pK a 0 The value is determined by its corresponding simplest organic molecule, such as the pK of the alco...

Embodiment 2

[0080] Take p-chloroaniline as an example ( figure 2 ):

[0081]a. First identify the dissociation center, and use the method based on substructure matching to query NH 3 +, corresponding to the dissociation center aniline (ID: 17) in Table 1, pK a 0 The value is 5.17. build as figure 2 Molecular junction tree shown, dissociation center NH 3 + is the 0th layer (i=0).

[0082] b. According to the electronic effect constant (σ) table and electronic effect transfer parameter (γ) table defined in Tables 2 and 3, use the method based on substructure matching to query and obtain the σ and γ values ​​corresponding to the atomic types of each layer.

[0083] c. To calculate the contribution of the 5th layer (i=5) atoms to the electronic effect of the dissociation center, first determine the atoms in the 5th layer (1 in total, the atom type is chlorine, where i=5, j=1) ; Look up Table 2 to get the electron effect constant σ of the atom 5，1 =6.39 (ID: 26); this atom involves t...

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Abstract

The invention relates to a brand new method for predicting the acid-base dissociation constant (pKa) of organic small molecules based on a hierarchical atom additive model. Based on the linear relationship rule of free energy changes of acid-base dissociation balance at a given temperature, the method firstly establishes the hierarchical atom additive model based on a Hammett-Taft equation and a processed substituent effect of 'dissociation center-rest part' brought forward by Cherkasov and the like, and then calculates the acid-base dissociation constant (pKa) value of a corresponding compound according to the concrete structure of the compound through the model. The method does not have the difficulties of large number of substituent electronic effect constants and correction factors relating existing in the prior method, ensures the speediness and accuracy of the prediction, shows good data fitting and predictive ability on a plurality of sample sets, breaks through the prior method which studies the drug pKa at an early research and development stage of a new drug, reduces the drug research and development cost on a large scale, and improves the discovery efficiency of the new drug.

Description

technical field [0001] The present invention relates to a novel molecular acid-base dissociation constant prediction method based on layered atomic summation model, which is suitable for virtual in vitro high-throughput absorption, distribution, metabolism, excretion, etc. of the compound according to the molecular structure information of the compound ( Evaluation and screening of ADME) properties. Background technique [0002] Traditional drug design often focuses on the activity of the compound (generally in vivo activity) first, and then the pharmacokinetic characteristics of the compound ( figure 1 ). However, with the continuous enhancement of the ability to discover active compounds and the deepening of ADME research, this traditional and inefficient serial drug development process can no longer meet the needs of modern drug development. Instead, a more efficient parallelized drug development process ( figure 1 ). In the parallel process, multiple properties of dr...

Claims

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Application Information

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IPC IPC(8): G01N33/15G06F19/00G06F19/10
Inventor 蒋华良罗小民朱维良陈凯先郑明月
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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