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BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR
Stereochemistry is an important determinant of a molecule’s biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently thre...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805266/ https://www.ncbi.nlm.nih.gov/pubmed/22907158 http://dx.doi.org/10.3390/molecules17089971 |
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author | Sliwoski, Gregory Lowe, Edward W. Butkiewicz, Mariusz Meiler, Jens |
author_facet | Sliwoski, Gregory Lowe, Edward W. Butkiewicz, Mariusz Meiler, Jens |
author_sort | Sliwoski, Gregory |
collection | PubMed |
description | Stereochemistry is an important determinant of a molecule’s biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS) that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF) determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r(2) = 0.89, q(2) = 0.78). Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS) for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891). |
format | Online Article Text |
id | pubmed-3805266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-38052662013-10-22 BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR Sliwoski, Gregory Lowe, Edward W. Butkiewicz, Mariusz Meiler, Jens Molecules Article Stereochemistry is an important determinant of a molecule’s biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS) that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF) determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r(2) = 0.89, q(2) = 0.78). Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS) for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891). MDPI 2012-08-20 /pmc/articles/PMC3805266/ /pubmed/22907158 http://dx.doi.org/10.3390/molecules17089971 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Sliwoski, Gregory Lowe, Edward W. Butkiewicz, Mariusz Meiler, Jens BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title | BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title_full | BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title_fullStr | BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title_full_unstemmed | BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title_short | BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR |
title_sort | bcl::emas — enantioselective molecular asymmetry descriptor for 3d-qsar |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805266/ https://www.ncbi.nlm.nih.gov/pubmed/22907158 http://dx.doi.org/10.3390/molecules17089971 |
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