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Molecules 2016, 21(11), 1554; doi:10.3390/molecules21111554

Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors

1
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
2
Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
*
Author to whom correspondence should be addressed.
Academic Editor: James W. Gauld
Received: 12 October 2016 / Revised: 10 November 2016 / Accepted: 11 November 2016 / Published: 17 November 2016
(This article belongs to the Section Theoretical Chemistry)
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Abstract

The crystallized ligands in the Protein Data Bank (PDB) can be treated as the inverse shapes of the active sites of corresponding proteins. Therefore, the shape similarity between a molecule and PDB ligands indicated the possibility of the molecule to bind with the targets. In this paper, we proposed a shape similarity profile that can be used as a molecular descriptor for ligand-based virtual screening. First, through three-dimensional (3D) structural clustering, 300 diverse ligands were extracted from the druggable protein–ligand database, sc-PDB. Then, each of the molecules under scrutiny was flexibly superimposed onto the 300 ligands. Superimpositions were scored by shape overlap and property similarity, producing a 300 dimensional similarity array termed the “Three-Dimensional Biologically Relevant Spectrum (BRS-3D)”. Finally, quantitative or discriminant models were developed with the 300 dimensional descriptor using machine learning methods (support vector machine). The effectiveness of this approach was evaluated using 42 benchmark data sets from the G protein-coupled receptor (GPCR) ligand library and the GPCR decoy database (GLL/GDD). We compared the performance of BRS-3D with other 2D and 3D state-of-the-art molecular descriptors. The results showed that models built with BRS-3D performed best for most GLL/GDD data sets. We also applied BRS-3D in histone deacetylase 1 inhibitors screening and GPCR subtype selectivity prediction. The advantages and disadvantages of this approach are discussed. View Full-Text
Keywords: BRS-3D; molecular similarity profile; QSAR; SVM; ligand-based virtual screening; subtype selectivity BRS-3D; molecular similarity profile; QSAR; SVM; ligand-based virtual screening; subtype selectivity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Hu, B.; Kuang, Z.-K.; Feng, S.-Y.; Wang, D.; He, S.-B.; Kong, D.-X. Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors. Molecules 2016, 21, 1554.

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