Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
J Chem Inf Model. 2024 Apr 22;64(8):3451-3464. doi: 10.1021/acs.jcim.4c00089. Epub 2024 Apr 9.
Cytochrome P450 3A4 (CYP3A4) is one of the most important drug-metabolizing enzymes in the human body and is well known for its complicated, atypical kinetic characteristics. The existence of multiple ligand-binding sites in CYP3A4 has been widely recognized as being capable of interfering with the active pocket through allosteric effects. The identification of ligand-binding sites other than the canonical active site above the heme is especially important for understanding the atypical kinetic characteristics of CYP3A4 and the intriguing association between the ligand and the receptor. In this study, we first employed mixed-solvent molecular dynamics (MixMD) simulations coupled with the online computational predictive tools to explore potential ligand-binding sites in CYP3A4. The MixMD approach demonstrates better performance in dealing with the receptor flexibility compared with other computational tools. From the sites identified by MixMD, we then picked out multiple sites for further exploration using ensemble docking and conventional molecular dynamics (cMD) simulations. Our results indicate that three extra sites are suitable for ligand binding in CYP3A4, including one experimentally confirmed site and two novel sites.
细胞色素 P450 3A4（CYP3A4）是人体内最重要的药物代谢酶之一，以其复杂的、非典型的动力学特性而闻名。CYP3A4 中多个配体结合位点的存在被广泛认为能够通过别构效应干扰活性口袋。除了血红素上方的典型活性位点之外，鉴定其他配体结合位点对于理解 CYP3A4 的非典型动力学特性以及配体与受体之间的有趣关联尤为重要。在这项研究中，我们首先采用混合溶剂分子动力学（MixMD）模拟与在线计算预测工具相结合，探索 CYP3A4 中的潜在配体结合位点。与其他计算工具相比，MixMD 方法在处理受体灵活性方面表现出更好的性能。从 MixMD 确定的位点中，我们然后使用集合对接和传统分子动力学（cMD）模拟选择了多个进一步探索的位点。我们的结果表明，CYP3A4 中有三个额外的位点适合配体结合，包括一个实验证实的位点和两个新的位点。
