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

Abstract

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 Q 2 = 0.658, R 2 = 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 Q 2 = 0.666, R 2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 = 0.721, R 2 = 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, OPEN ACCESSMolecules 2015, 20 1015 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.

Identification of the Structural Features of Guanine Derivatives as MGMT Inhibitors Using 3D-QSAR Modeling Combined with Molecular Docking

“…Since the five CoMSIA descriptor fields—namely steric (S), electrostatic (E), hydrophobic (H), hydrogen bond donor (D) and acceptor (A)—are not totally independent from each other, different combinations of the five fields were used to obtain the best model [34,40,41]. The results of the 31 possible field combinations were shown in Figure 1 and the Q cv 2 value was used to assess the statistical qualities of these 3D-QSAR models.…”

“…Three-dimensional quantitative structure activity relationship (3D-QSAR) describes the linkage between the structural features and the bioactivities of compounds and also points to suggestions for designing novel inhibitors of enzymes [31,32,33,34]. Comparative molecular field analysis (CoMFA) has become one of the most widely used 3D-QSAR methods in rational drug design since it was first introduced by Cramer et al in 1988 [35].…”

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study

“…Molecular docking was conducted using the Surflex-Dock module in the SYBYL-X 1.3 software (Tripos, Inc., St. Louis, MO, USA) [32,33,34,35]. All 320 molecules from our in-house natural compound database were downloaded from the PubChem database () in mol2 format.…”

Lipophilic Metabolic Efficiency (LipMetE) and Drug Efficiency Indices to Explore the Metabolic Properties of the Substrates of Selected Cytochrome P450 Isoforms

“…11 Toward this goal, various authors in the past used several ligand- 12 as well as structure-based in silico approaches 13,14 and hybrid methods 15,16 for toxicological profiling of lead candidates. These include QSAR, 17,18 machine-learning methods, 19,20 pharmacophore-based methods, 21,22 shape-focused approaches, molecular interaction fields (MIFs), 23 reactivity-focused techniques, 24 docking 25,26 and molecular dynamics (MD) simulation studies on different classes of modulators of CYP450, ABC transporters, and the hERG K + ion channel. 27−30 Additionally, the impact of lipophilicity on membrane permeability, bioavailability, promiscuity, drug metabolism by CYP450s, and overall ADME-Tox properties has also been reported by several authors in the past.…”