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Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database.

作者信息

Avdeef Alex

机构信息

in-ADME Research, 1732 First Avenue #102, New York, NY 10128 USA.

出版信息

ADMET DMPK. 2020 Mar 4;8(1):29-77. doi: 10.5599/admet.766. eCollection 2020.


DOI:10.5599/admet.766
PMID:35299775
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8915599/
Abstract

The accurate prediction of solubility of drugs is still problematic. It was thought for a long time that shortfalls had been due the lack of high-quality solubility data from the chemical space of drugs. This study considers the quality of solubility data, particularly of ionizable drugs. A database is described, comprising 6355 entries of intrinsic solubility for 3014 different molecules, drawing on 1325 citations. In an earlier publication, many factors affecting the quality of the measurement had been discussed, and suggestions were offered to improve ways of extracting more reliable information from legacy data. Many of the suggestions have been implemented in this study. By correcting solubility for ionization (i.e., deriving intrinsic solubility, S) and by normalizing temperature (by transforming measurements performed in the range 10-50 °C to 25 °C), it can now be estimated that the average interlaboratory reproducibility is 0.17 log unit. Empirical methods to predict solubility at best have hovered around the root mean square error (RMSE) of 0.6 log unit. Three prediction methods are compared here: (a) Yalkowsky's general solubility equation (GSE), (b) Abraham solvation equation (ABSOLV), and (c) Random Forest regression (RFR) statistical machine learning. The latter two methods were trained using the new database. The RFR method outperforms the other two models, as anticipated. However, the ability to predict the solubility of drugs to the level of the quality of data is still out of reach. The data quality is not the limiting factor in prediction. The statistical machine learning methodologies are probably up to the task. Possibly what's missing are solubility data from a few sparsely-covered chemical space of drugs (particularly of research compounds). Also, new descriptors which can better differentiate the factors affecting solubility between molecules could be critical for narrowing the gap between the accuracy of the prediction models and that of the experimental data.

摘要

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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Perspectives in solubility measurement and interpretation.

ADMET DMPK. 2019-4-5

[2]
Solubility Challenge Revisited after Ten Years, with Multilab Shake-Flask Data, Using Tight (SD ∼ 0.17 log) and Loose (SD ∼ 0.62 log) Test Sets.

J Chem Inf Model. 2019-5-9

[3]
Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates.

Eur J Pharm Sci. 2019-3-23

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Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration.

Pharmaceutics. 2018-11-17

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Investigating the effects of amphipathic gastrointestinal compounds on the solution behaviour of salt and free base forms of clofazimine: An in vitro evaluation.

Int J Pharm. 2018-9-17

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Human intestinal fluid factors affecting intestinal drug permeation in vitro.

Eur J Pharm Sci. 2018-6-15

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Solubility determination of raloxifene hydrochloride in ten pure solvents at various temperatures: Thermodynamics-based analysis and solute-solvent interactions.

Int J Pharm. 2018-4-18

[8]
Effect of vinylpyrrolidone polymers on the solubility and supersaturation of drugs; a study using the Cheqsol method.

Eur J Pharm Sci. 2018-2-23

[9]
Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device.

Sci Rep. 2018-2-13

[10]
Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System-Biowaiver.

J Pharm Sci. 2018-2-6

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