Jaladanki Chaitanya K, Gahlawat Anuj, Rathod Gajanan, Sandhu Hardeep, Jahan Kousar, Bharatam Prasad V
Department of Medicinal Chemistry and Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab, India.
Drug Metab Rev. 2020 Aug;52(3):366-394. doi: 10.1080/03602532.2020.1765792. Epub 2020 Jul 9.
Cytochromes P450 are oxidizing enzymes; a few families of cytochromes P450 are implicated in drug metabolism. These enzymatic reactions involve many processes including (i) prodrug to drug conversion, (ii) easy excretion of drug, (iii) generation of reactive metabolites, many of which cause toxicity. In this review, the fundamental biochemical mechanisms associated with the conversion of drugs into the useful or toxic metabolites have been discussed. The mechanisms can be established with the help of many experimental methods like mass spectral analysis, NMR and analysis etc. Computational methods provide detailed atomic level information, which is generally not available from experimental studies. Thus, the efforts in elucidating the molecular mechanisms are complementary to the known experimental methods and are often clearer (especially in providing 3D information about the metabolites and their reactions). Quantum chemical methods and molecular docking become especially very useful. This review includes five case studies, which explain how the atomic level details were obtained to explore the reaction mechanisms of drug metabolism by cytochromes P450.
细胞色素P450是氧化酶；少数细胞色素P450家族与药物代谢有关。这些酶促反应涉及许多过程，包括（i）前药向药物的转化，（ii）药物的易排泄，（iii）活性代谢物的生成，其中许多会导致毒性。在本综述中，已经讨论了与药物转化为有用或有毒代谢物相关的基本生化机制。这些机制可以借助许多实验方法来确定，如质谱分析、核磁共振和分析等。计算方法提供详细的原子水平信息，这通常是实验研究无法获得的。因此，阐明分子机制的努力与已知的实验方法相辅相成，并且往往更清晰（特别是在提供代谢物及其反应的三维信息方面）。量子化学方法和分子对接变得尤其有用。本综述包括五个案例研究，解释了如何获得原子水平的细节以探索细胞色素P450的药物代谢反应机制。
