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Integration of mutational and molecular docking studies: An in silico approach to assess the stability and binding potential of CYP3A4

CYP3A4 is a major cytochrome P450 liable for almost half of CYP450 mediated Phase 1 drug metabolism. Because of its broad substrate specificity and high level of expression in the liver this enzyme plays a dominant role in drug metabolism. This study aimed to investigate the influence of single amino acid substitution on protein structural stability and ligand binding affinity through docking studies. Single site mutations are created in the CYP3A4 sequence and checked all the sites for the favorable and stable mutations using CUPSAT and SDM tools. Based on the results of CUPSAT and SDM tools, three mutations (H65R, D154E, and K422N) were found to be more favorable and stable, hence modeled using DS modeler. Docking studies were carried out for wild and mutant modeled structures with the compounds Imipramine, Midazolam, Nifedipine, and Quinidine using DS libdock. The docking results suggested that the H65R, D154E, and K422N having a docking scores of 121.907, 121.658, and 134.605, respectively, are more significant in comparison to wild CYP3A4 (87.126). Among the three mutated models, K422N mutant has been identified as more stable as supported by stability and docking assessment and may be taken into consideration for further in vitro studies.