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Molecules 2015, 20(1), 1014-1030; doi:10.3390/molecules20011014

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

1
School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
2
College of Bioengineering, Chongqing University, Chongqing 400044, China
3
School of Chemistry and Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China
4
School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Iwao Ojima
Received: 11 September 2014 / Accepted: 29 November 2014 / Published: 9 January 2015
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
View Full-Text   |   Download PDF [2411 KB, uploaded 9 January 2015]   |  

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. View Full-Text
Keywords: CYP11B1 inhibitors; 3D-QSAR; pharmacophore model; Cushing’s syndrome CYP11B1 inhibitors; 3D-QSAR; pharmacophore model; Cushing’s syndrome
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Yu, R.; Wang, J.; Wang, R.; Lin, Y.; Hu, Y.; Wang, Y.; Shu, M.; Lin, Z. Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors. Molecules 2015, 20, 1014-1030.

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