Inhibitory activity of Imidazole with Cytochrome P450 2B4: A Docking and Molecular Dynamics Study
Authors: Siddharth Sinha1, Arpit Tandon2
Authors affiliation: 1. ACS- Bioinformatics, Biotech Park, Lucknow, India. 2.Amity Institute of Biotechnology, Amity University, Lucknow, India.
Email: srs14_02@hotmail.com
Supervisor: Daya S. Srivastava
Supervisor affiliation: Central Drug Research Institute, Lucknow, India
Dates: Received on: 6 February 2010, Accepted on: 7 March 2010, Published on 27 March 2010
Article type: Bioinformatics
Abstract
In order to analyze binding of imidazole inhibitors with CYP2B4 enzyme, molecular docking and dynamics study was performed using AutoDock4 and Gromacs. Twenty seven imidazole inhibitors were selected on the basis of structural similarity and were docked to the crystal structure of the enzyme (PDB ID: 2BDM). Molecular dynamics studies were then performed to find out the stability of selected imidazole-CYP2B4 complexes. Our docking results indicated that residues THR302, GLY299, GLU301 construct the active pocket of CYP2B4 by forming hydrogen bonds to cause inhibitory behavior. On the basis of binding energies, compounds flutrimazole, sertaconazole, isoconazole, miconazole were selected which give better binding energies and inhibition constants than the reference bifonazole. In addition to this, compounds sertaconazole and isoconazole showed hydrogen bond with Thr-302 active site. Molecular dynamics simulation, based on the docking results, implies that the orientation of imidazole in the active pocket show different stabilities when performed for a time period of 70ps. Orientation of bifonazole, sertaconazole, and flutrimazole demonstrated hydrogen bond with residue THR-302 and gradually reach dynamic equilibrium resulting in stable dynamic complex. While the two imidazole-CYP2B4 complex (isoconazole- CYP2B4, miconazole- CYP2B4 complex) reveals an unstable binding mode with CYP 2B4, as they induced conformation strains in the enzyme during the dynamic simulation.
Citation
Siddharth Sinha1, Arpit Tandon, Daya S. Srivastava, Inhibitory activity of Imidazole with Cytochrome P450 2B4: A Docking and Molecular Dynamics Study, Biofrontiers (2010) vol.1, Issue.2: Pg 48-61
| Publisher | Biofrontier Publications |
| ISSN | 0975-4865 |
| Copyright | Author |
| License | Creative Commons Attribution-Noncommercial 3.0 Unported License |
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