title: Combined pharmacophore modeling, 3D-QSAR, homology modeling and docking studies on CYP11B1 inhibitors.
abstract: The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing's syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q2 = 0.658, R2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q2 = 0.666, R2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q2 = 0.721, R2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing's syndrome treatment.
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. 379490507@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing 400044, China. wangjuan7986@126.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. wangrx1022@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Chemistry and Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China. linyong@cqut.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. huy@cqut.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. wangyqnn@cqut.edu.cn.
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. sm7507@126.com.
authors.forename: Mao
authors.initials: M
authors.lastname: Shu
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. zhlin@cqut.edu.cn.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D013252:Steroid 11-beta-Hydroxylase