Abstract：
The unmarked potential drug molecule azamulin has been found to be a specific inhibitor of CYP3A4 and CYP3A5 in recent years, but this molecule also shows different binding ability and affinity to the two CYP3A isoforms. In order to explore the microscopic mechanism, conventional molecular dynamics (MD) simulation methods were performed to study the dynamic interactions between two isoforms and azamulin. The simulation results show that the binding of the ligand leads to different structural properties of two CYP3A proteins. First of all, compared with apo-CYP3A4, the binding of the ligand azamulin can lead to changes in the structural flexibility of CYP3A4, i.e., holo-CYP3A4 is more flexible than apo-CYP3A4. The structural changes of CYP3A5 are just the opposite. The ligand binding increases the rigidity of CYP3A5. Furthermore, the representative structures of the production phase in the MD simulation were in details analyzed to obtain the microscopic interactions between the ligand azamulin and two CYP3A isoforms at the atomic level. It is speculated that the difference of composition and interaction of the active sites is the fundamental cause of the change of structural properties of the two proteins.Communicated by Ramaswamy H. Sarma.
摘要：
近年来发现无标记的潜在药物分子azamulin是CYP3A4和CYP3A5的特异性抑制剂,但该分子也显示出与两种CYP3A亚型不同的结合能力和亲和力。为了探索微观机理,采用常规分子动力学(MD)模拟方法研究了两种同工型与氮丙素之间的动态相互作用。模拟结果表明，配体的结合导致两种CYP3A蛋白的结构性质不同。首先,与apo-CYP3A4相比，配体azamulin的结合可以导致CYP3A4结构柔性的变化，即holo-CYP3A4比apo-CYP3A4更灵活。CYP3A5的构造变更正好相反。配体结合增加CYP3A5的刚性。此外，详细分析了MD模拟中生产阶段的代表性结构，以获得配体氮丙素和两种CYP3A同工型在原子水平上的微观相互作用。推测活性位点组成和相互作用的差异是两种蛋白质结构性质变化的根本原因。由RamaswamyH.Sarma沟通。
