title: A pharmacophore model specific to active site of CYP1A2 with a novel molecular modeling explorer and CoMFA.
abstract: Comparative molecular field analysis (CoMFA) is a widely used 3D-QSAR method by which we can investigate the potential relation between biological activity of compounds and their structural features. In this study, a new application of this approach is presented by combining the molecular modeling with a new developed pharmacophore model specific to CYP1A2 active site. During constructing the model, we used the molecular dynamics simulation and molecular docking method to select the sensible binding conformations for 17 CYP1A2 substrates based on the experimental data. Subsequently, the results obtained via the alignment of binding conformations of substrates were projected onto the active- site residues, upon which a simple blueprint of active site was produced. It was validated by the experimental and computational results that the model did exhibit the high degree of rationality and provide useful insights into the substrate binding. It is anticipated that our approach can be extended to investigate the protein-ligand interactions for many other enzyme-catalyzed systems as well.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, P. R. 200240, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Wei
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D019388:Cytochrome P-450 CYP1A2