Computational screening for active compounds targeting protein sequences: methodology and experimental validation

Fei Wang; Dongxiang Liu; Heyao Wang; Cheng Luo; Mingyue Zheng; Hong Liu; Weiliang Zhu; Xiaomin Luo; Jian Zhang; Hualiang Jiang

doi:10.1021/ci200264h

Computational screening for active compounds targeting protein sequences: methodology and experimental validation

J Chem Inf Model. 2011 Nov 28;51(11):2821-8. doi: 10.1021/ci200264h. Epub 2011 Oct 11.

Authors

Fei Wang¹, Dongxiang Liu, Heyao Wang, Cheng Luo, Mingyue Zheng, Hong Liu, Weiliang Zhu, Xiaomin Luo, Jian Zhang, Hualiang Jiang

Affiliation

¹ 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.

PMID: 21955088
DOI: 10.1021/ci200264h

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cloning, Molecular
Computational Biology / methods*
Computational Biology / statistics & numerical data
Databases, Factual
Drug Discovery
Escherichia coli
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / chemistry*
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 beta
HEK293 Cells
Humans
Ligands
Models, Chemical*
Protein Binding
Receptors, G-Protein-Coupled / antagonists & inhibitors
Receptors, G-Protein-Coupled / chemistry*
Receptors, G-Protein-Coupled / genetics
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry*
Recombinant Proteins / genetics
Sirtuin 1 / antagonists & inhibitors
Sirtuin 1 / chemistry*
Sirtuin 1 / genetics
Small Molecule Libraries / chemistry*
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology
Support Vector Machine
Transfection
Transformation, Bacterial
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / chemistry*
p38 Mitogen-Activated Protein Kinases / genetics

Substances

FFAR1 protein, human
Ligands
Receptors, G-Protein-Coupled
Recombinant Proteins
Small Molecule Libraries
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
p38 Mitogen-Activated Protein Kinases
Glycogen Synthase Kinase 3
SIRT1 protein, human
Sirtuin 1