title: A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors.
abstract: B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.
authors.affiliation: Department of Chemistry, Yunnan University, Kunming 650091, China. front701228.student@sina.com.|Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China. front701228.student@sina.com.
authors.forename: Huiding
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China. chenglijun1414@126.com.
authors.forename: Lijun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Yunnan University, Kunming 650091, China. zjq1986526@21cn.com.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Yunnan University, Kunming 650091, China. xgxie@ynu.edu.cn.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China. chenneyao16@hotmail.com.
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Qiu
authors.affiliation: Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China. fujj920@163.com.
authors.forename: Jijun
authors.initials: J
authors.lastname: Fu
mesh_terms: D000465:Algorithms; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048493:Proto-Oncogene Proteins B-raf
keywords: 3D QSAR; B-Raf inhibitors; imidazopyridine; pharmacophore; virtual screening