An In-Depth Investigation of Cytochrome P۴۵۰ ۳A۴ Inhibitors: Unveiling Key Structural Features and Their Impact

Cytochromes (CYP) are key players in the oxidation of xenobiotics, significantly influencing drug safety, persistence, bioactivation, and interactions between drugs and food. This study aims to develop various computational models to predict interactions of inhibitors with one of the most important CYP isoforms, CYP۳A۴. In this research, a dataset of CYP۳A۴ inhibitors was created from literature and QSAR model, HQSAR and binary QSAR model along with docking analysis, were successfully employed to investigate critical features of CYP۳A۴ inhibitors. A validation method was implemented to assess the accuracy of the results. The findings indicate that the energy of interaction and the overall shape of the molecules play significant roles in the inhibitory effect. Important fragments for inhibitory activity were discovered using hologram model. The docking analysis identified key amino acids in CYP۳A۴ that are crucial for binding the inhibitors, including Phe۵۷, Asp۷۶, Arg۱۰۶, Arg۱۰۵, Phe۲۲۰, Phe۱۰۸, Ala۳۷۰, Ser۱۱۹, and Leu۴۸۲. Accurate and precise models were created using chemometric methods. The q۲ and Z-score obtained for QSAR models showed that using these findings would be beneficial in drug design with little or no inhibitory effect on CYP۳A۴.

کلیدواژه ها:

HQSAR ، QSAR ، CYP۳A۴ ، Docking ، Ketoconazole ، Inhibitor ، Metabolism