Study of the Structural Pathology Caused by CYP2C9 Polymorphisms towards Flurbiprofen Metabolism Using Molecular Dynamics Simulation

摘要: CYP2C9 is one of the major cytochrome P450 enzymes that play a crucial role in metabolic clearance several drugs current clinical used. has allelic variant forms each which arises from single amino acid substitution and could reduce/increase enzyme activities affect drug metabolism. Mutant alleles may cause serious toxicity some narrow therapeutic index drugs. CYP2C9*13, commonly found Asian population, Leu90Pro leads to defective metabolism individuals who carry this allele. It been reported activity CYP2C9*13 was reduced towards substrates compared wildtype. In study, X-ray crystal structure human 2C9 complexed with flurbiprofen (PDB code: 1R9O) represented wildtype constructed based on CYP2C9-flurbiprofen complex. Herein, molecular docking CYP2C9*1 performed search for orientation corresponds its binding state before undergoing monooxygenation. Subsequently, dynamics simulation operated compare catalytic cavity these 2 variants. Substrate access channel dramatic effect an interaction between enzyme. Consequently, study can lead understanding structural pathology caused by change variant.