title: Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors.
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.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. benhu917@gmail.com.|Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. benhu917@gmail.com.
authors.forename: Ben
authors.initials: B
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. kzk@webmail.hzau.edu.cn.|Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. kzk@webmail.hzau.edu.cn.
authors.forename: Zheng-Kun
authors.initials: ZK
authors.lastname: Kuang
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. fshiyu@webmail.hzau.edu.cn.
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. duke.e.wang@gmail.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. cencibaitai@webmail.hzau.edu.cn.
authors.forename: Song-Bing
authors.initials: SB
authors.lastname: He
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China. dxkong@mail.hzau.edu.cn.|Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. dxkong@mail.hzau.edu.cn.
authors.forename: De-Xin
authors.initials: DX
authors.lastname: Kong
mesh_terms: D003198:Computer Simulation; D030562:Databases, Protein; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry; D040681:Structural Homology, Protein; D060388:Support Vector Machine
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: BRS-3D; QSAR; SVM; ligand-based virtual screening; molecular similarity profile; subtype selectivity