The mitochondrial cytochrome P450 enzymes inhibitor steroid 11-hydroxylase\n(CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an\neffect in the treatment of Cushing�s syndrome. A pharmacophore model generated by\nGenetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets\n(GALAHAD) was used to align the compounds and perform comparative molecular field\nanalysis (CoMFA) with Q2 = 0.658, R2 = 0.959. The pharmacophore model contained six\nhydrophobic regions and one acceptor atom, and electropositive and bulky substituents\nwould be tolerated at the A and B sites, respectively. A three-dimensional quantitative\nstructure-activity relationship (3D-QSAR) study based on the alignment with the atom root\nmean square (RMS) was applied using comparative molecular field analysis (CoMFA)\nwith Q2 = 0.666, R2 = 0.978, and comparative molecular similarity indices analysis\n(CoMSIA) with Q2 = 0.721, R2 = 0.972. These results proved that all the models have good\npredictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated\nthat 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)\nmodel of the CYP11B1 was generated based on the crystal structure of the CYP11B2\n(PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was\nemployed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The\ndocking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds\nwith the amino group of residue Arg155 and Arg519, which suggested that an\nelectronegative substituent at these positions could enhance the activities of compounds.\nAll the models generated by GALAHAD QSAR and Docking methods provide guidance\nabout how to design novel and potential drugs for Cushing�s syndrome treatment.
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