title: Multiple-docking and affinity fingerprint methods for protein classification and inhibitors selection.
abstract: The function-based protein classification holds tremendous promise for molecular recognition and the structure-based design process. We describe here a new strategy combined with multiple-docking tools and "affinity fingerprint" analysis technology to detect functional relationships among proteins based on the substrate binding features and protein-ligand interaction matrix and apply it successfully for the family of phospholipase A2 to investigate protein-ligand binding, function-based protein classification, and inhibitor selection, evaluation. Binding data and matrix were generated by multiple versus multiple-docking among 12 PLA2s and 84 PLA2 inhibitors. Three kinds of statistic techniques, principal component analysis, multidimensional scaling, and cluster algorithms, were chosen to distinguish the groups with similar binding characteristics. The 12 PLA2s were automatically categorized into reasonable subfamilies on the basis of the protein-ligand binding matrix, and the classifying problem of cPLA2 (PDB ID: 1CJY ) with relatively low homology was successfully dealt with. This approach was also used to identify and group the selective inhibitors against human nonpancreatic sPLA2. A sound pharmacophore has been defined from these selective inhibitors. It shows that the method is quite robust against individual data deviation, especially false positive, which makes it possible to be used in virtual screening with large enzyme families to generate selective inhibitors of targets on the basis of limited structural/function information.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000737:chemistry / Q000378:metabolism*; D025341:Principal Component Analysis; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2