title: QM/MM based 3D QSAR models for potent B-Raf inhibitors.
abstract: Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives, were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q (2) = 0.624, r (2) = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields was also derived (q (2) = 0.590, r (2) = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r (2) values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features responsible for increasing biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results can offer useful information for the design of new B-Raf inhibitors.
authors.affiliation: Department of Biotechnology and Bioinformatics, Korea University, Jochiwon-Eup, Yeongi-Gun, Chungnam 339-700, Korea.
authors.forename: Jae Yoon
authors.initials: JY
authors.lastname: Chung
authors.forename: Hwan Won
authors.initials: HW
authors.lastname: Chung
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Hah
authors.forename: Art E
authors.initials: AE
authors.lastname: Cho
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D055672:Static Electricity
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf