抑制剂RN-486与BTK靶标作用机理的分子动力学研究

Insight into Interaction Mechanism of Inhibitor RN-486 to BTK Target by Using Molecular Dynamics Simulation

摘要: 布鲁顿式酪氨酸激酶(Bruton’s tyrosine kinase)是近来治疗B细胞恶性肿瘤的明星靶点，在很多疾病和信号通路中起着关键作用，现已成为药物的研发热点。搞清楚BTK-抑制剂之前的相互作用及关键作用残基对药物的研发是十分必要的，本文选择罗氏药业公司开发的BTK抑制剂(研发代号为RN-486)，使用MM/GBSA方法以及正则模式熵来计算靶标与抑制剂的结合自由，同时采用基于残基的自由能分解方法评估主要残基对抑制剂结合的贡献。结果发现，RN-486与靶标结合的能量主要以疏水相互作用和静电相互作用为主，其中，LEU408和VAL416为两个重要的疏水残基，与RN-486发生范德华相互作用，而LYS430、TYR476和ASP539三个带电残基与RN-486发生静电相互作用。结合计算数据，我们找到了抑制剂与靶标的主要结合位点与作用形式，这为后期继续设计和开发BTK靶标的抑制剂提供根据指向性的理论指导。

Abstract: Bruton’s tyrosine kinase (BTK) is becoming an increasingly attractive target for drug discovery due to its critical role in multiple pathways and a variety of diseases. Understanding the binding mech-anism and key residues in BTK-inhibitor interaction is crucial for effective drug discovery. In this study, a BTK inhibitor developed by Roche (RN-486) was selected. The MM/GBSA method and the normal mode entropy were used to calculate the binding free energy between the target and the inhibitor. Meanwhile, Residue-based free energy decomposition method was used to reveal the contribution of the major residues. The results showed that the binding mainly from hydrophobic interaction and electrostatic interaction. Leu408 and Val416 were two important hydrophobic res-idues, which had van der Waals interaction with RN-486. The charged residues Lys430, Tyr476 and Asp539 interact with RN-486 electrically. The results indicate that the main binding sites and in-teraction mechanism between inhibitor and target, which are expected to provide theoretical guidance for the subsequent design and development of inhibitors targeting BTK.