Abstract Description

Cytochrome P450 3A4 (CYP3A4) metabolizes over 50% of clinically administered drugs. The enzyme shows high hepatic and gastrointestinal abundance, making it the most important CYP enzyme. Genetic variants of CYP3A4, which influence drug bioavailability and systemic clearance, are poorly characterized, with no definitive clinical phenotypes due to substrate selectivity in metabolic profiles. This results in unguided personalized treatment for drugs metabolized by the enzyme. Importantly, CYP3A4*15 variant is identified as Afrocentric, with frequencies higher than any other variant globally. Studies show that CYP3A4*15 affects the metabolism of drugs such as quinine, artemether, lumefantrine, amodiaquine, which are anti-malarials, and amiodarone used for cardiac arrhythmias; and therefore, important for African endemic diseases. This study leverages high-performance computing and the GROMACS all-atom molecular dynamics (MD) simulations to characterize altered structural dynamics of the resultant missense mutation. Triplicate 500 ns long independent MD simulations for the reference and variant enzymes were performed to ensure reproducibility. From post-MD analysis, a rare process markedly, substantial loss in heme interactions with Arg105, was captured in one of the mutant runs, lacking in the other two. We performed further analysis to elucidate this using dynamic residue network analysis and dynamics allostery techniques. This revealed a distinct mutation-induced allosteric modulation that could have driven the observation. The findings underscore the importance of computational approaches in understanding the molecular mechanisms of altered enzyme dynamics affecting drug metabolism and pave the way for strategic personalized medicine.