title: Computational screening for active compounds targeting protein sequences: methodology and experimental validation.
abstract: The three-dimensional (3D) structures of most protein targets have not been determined so far, with many of them not even having a known ligand, a truly general method to predict ligand-protein interactions in the absence of three-dimensional information would be of great potential value in drug discovery. Using the support vector machine (SVM) approach, we constructed a model for predicting ligand-protein interaction based only on the primary sequence of proteins and the structural features of small molecules. The model, trained by using 15,000 ligand-protein interactions between 626 proteins and over 10,000 active compounds, was successfully used in discovering nine novel active compounds for four pharmacologically important targets (i.e., GPR40, SIRT1, p38, and GSK-3β). To our knowledge, this is the first example of a successful sequence-based virtual screening campaign, demonstrating that our approach has the potential to discover, with a single model, active ligands for any protein.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
authors.forename: Heyao
authors.initials: H
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D001665:Binding Sites; D003001:Cloning, Molecular; D019295:Computational Biology / Q000379:methods* / Q000706:statistics & numerical data; D016208:Databases, Factual; D055808:Drug Discovery; D004926:Escherichia coli; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D060388:Support Vector Machine; D014162:Transfection; D014169:Transformation, Bacterial; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
chemical_list: C473034:FFAR1 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1