Cytochrome P450 enzymes (P450s) are a large superfamily of heme-containing monooxygenases central to metabolizing drugs, xenobiotics, and endogenous compounds. Their ability to catalyze selective oxidation reactions under physiological conditions has made them a major focus in pharmacology, toxicology, and biochemistry. However, the complexity of their active sites—characterized by flexibility, a short-lived reactive species Compound I, and multiple redox states—poses challenges for mechanistic understanding. Techniques such as X-ray crystallography and spectroscopy have provided insights into P450 structure and function, but mostly on resting state structures, while little experimental data has covered the reactive intermediates. Complementary computational approaches, including molecular dynamics (MD), density functional theory (DFT), quantum mechanics/molecular mechanics (QM/MM), and machine learning, are powerful tools for exploring dynamics, substrate recognition, and catalysis that will assist experimental studies in the field.

The goal of this Research Topic is to present cutting-edge research that advances our understanding of P450s through the integration of experimental and computational approaches. By bringing together contributions from structural biology, enzymology, spectroscopy, computational chemistry, and systems biology, this issue aims to highlight the multifaceted nature of P450 research and promote interdisciplinary collaboration. We welcome original research articles and reviews that explore P450 structure, dynamics, substrate specificity, catalytic mechanisms, and regulation, as well as reductases such as NADPH–cytochrome P450 reductase (CPR). This issue aspires to serve as a platform for researchers to share insights that bridge molecular-level understanding with broader biological and pharmacological implications, ultimately contributing to areas such as drug metabolism, enzyme engineering, and the development of P450-targeted therapeutics.

This Research Topic invites original research articles and reviews focused on cytochrome P450 enzymes, particularly studies that integrate or apply experimental and computational methodologies. Topics of interest include but are not limited to:

• P450 structure and dynamics

• Catalytic reaction mechanisms

• Substrate binding and selectivity

• Enzyme kinetics

• Drug metabolism

• Reaction intermediates

• Enzyme inhibition

• Enzyme engineering

Contributions employing techniques such as crystallography, spectroscopy, MD, DFT cluster models, QM/MM, and machine learning are encouraged.

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Computational Approaches to Study the Structure, Dynamics and Reactivity of Cytochrome P450 Enzymes