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Consideration of the stereochemical features of compounds in QSAR models. 2D+0.X molecular descriptors.
* 1 , 2 , 2
1  Odessa I,I,Mechnikov National University
2  NAS of Ukraine, A. V. Bogatsky Physico-Chemical Institute

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

Introduction: In chemoinformatics, stereochemical attributes are commonly taken into account only by direct description of spatial structures via 3D-QSAR approaches.  Usually these models are applied for one fixed conformer of each molecule. That can be undesirable if we don’t know the spatial structure of the molecule interacting with a biological target. In this study we show how to solve this problem in terms of simplex representation of the molecular structure (SiRMS).

Methods: In the SiRMS approach, every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition and structure). The advantages of that approach are the absence of "molecular alignment" problems, consideration of different physical-chemical properties of atoms (e.g. charge, lipophilicity, etc.), the high adequacy and good interpretability of obtained models and clear ways for  further molecular design. In this study, all molecular fragments which don’t determine stereochemistry of a molecule are described in terms of 2D molecular representation (structural formula). Structural elements which determine molecular stereoisomerism are described by  respective 3D chiral  conformation-independent simplexes  It should be noted that chiral simplexes allow us to describe the molecular system of any stereochemical complexity. In the proposal (2.0+0.X)D - QSAR approach parameter (0.X) is determined by the ratio of 2D achiral and 3D chiral simplexes included in the appropriate QSAR model. 

Results:To evaluate applicability of this approach, we had to solve some QSAR tasks with sets of compounds containing chirality. This approach allowed us to get valid QSAR models for data sets consisting of only compounds with one or more centers of chirality, of chiral and achiral compounds and of compounds with central and axial chirality as well. Use of simplex descriptors also allowed us to get structural and functional interpretation for those models. There was no situation where consensus QSAR model did not include some chiral descriptors, so, all of the studied properties are chirality-dependent.

Conclusion: Quality of those models is an evidence that  application of Simplex Representation of the Molecular Structure with described modification considering chirality is relatively simple and universal approach for obtaining adequate QSAR-models of chirality-dependent properties.

Keywords: QSAR, chirality, description, simplex, enantiomers