Computational studies on human cytochrome P450: advancing insights into drug metabolism

Understanding the catalytic functions of human cytochrome P450 enzymes (P450s) requires comprehensive and rigorous investigations of catalytic mechanisms using physics-based computational methods, such as the quantum mechanics/molecular mechanics (QM/MM) approach. These investigations deepen our mechanistic understanding of enzyme-catalyzed metabolic transformations, support the development of more accurate predictive models, and facilitate the rational design of safer and more effective drugs. However, existing computational studies remain limited compared with the broad chemical diversity of drug-like compounds and the structural and functional complexity of P450s, underscoring the need for further research. Moreover, elucidating the mechanisms of P450 inhibition and developing a systems-level understanding of P450 catalysis remain major challenges. This review summarizes recent advances and outlines future directions in the field.