高等学校化学学报 ›› 2019, Vol. 40 ›› Issue (9): 1918-1925.doi: 10.7503/cjcu20190261

• 物理化学 • 上一篇    下一篇

凝血因子Xa的S4口袋部分关键残基对利伐沙班结合的不同作用机制

瞿思颖,徐沁()   

  1. 上海交通大学生命科学技术学院, 微生物代谢国家重点实验室, 上海 200240
  • 收稿日期:2019-05-08 出版日期:2019-09-10 发布日期:2019-07-16
  • 通讯作者: 徐沁 E-mail:xuqin523@sjtu.edu.cn
  • 基金资助:
    国家自然科学基金(31770772)

Different Roles of Some Key Residues in the S4 Pocket of Coagulation Factor Xa for Rivaroxaban Binding

QU Siying,XU Qin()   

  1. State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology,Shanghai Jiao Tong University, Shanghai 200240, China
  • Received:2019-05-08 Online:2019-09-10 Published:2019-07-16
  • Contact: XU Qin E-mail:xuqin523@sjtu.edu.cn
  • Supported by:
    Supported by the National Natural Science Foundation of China(31770772)

摘要:

通过生物信息学对比、 分子动力学模拟和结合自由能计算分析了利伐沙班与凝血因子Xa的S4口袋部分关键残基之间动态相互作用的细节. 结果表明, 利伐沙班与凝血因子Xa结合不稳定是由S4口袋关键残基突变对疏水盒子完整性的破坏所致. 其中Trp215侧链的疏水作用对抑制剂结合的作用较大, 但对整体结构的影响短时间内较小. Tyr99虽然在结合自由能中贡献较小, 但其突变可能导致99 loop所在结构域的整体构象变化, 从而对于抑制剂或底物的结合特异性产生影响. S4口袋关键残基的不同作用在凝血因子Xa直接抑制剂的药物设计及其拮抗剂的开发中应予以充分考虑.

关键词: 凝血因子Xa, 利伐沙班, S4口袋, 分子动力学模拟, 结合自由能

Abstract:

The details of the dynamic interaction between rivaroxaban and some key residues in the S4 pocket of Coagulation factor X(FXa) were analyzed by bioinformatics alignment, molecular dynamics simulation and binding free energy calculation. The results indicated that the disruption of the hydrophobic S4 pocket caused by mutations in the key residues directly lower the binding affinity of rivaroxaban to FXa. The hydrophobic effect of the Trp215 side chain is more important in the inhibitor binding, but the effect on the overall structure is relatively minor in the limited time of simulations. Although Tyr99 contributes less in the binding free energy, its mutation may result in an overall conformational change in the domain where the 99 loop is located, thereby affecting the binding specificity of the inhibitor or substrate. The different roles of key residues in the S4 pocket should be fully considered in the drug design of the direct inhibitor of FXa and the development of its antagonists.

Key words: Coagulation factor Xa, Rivaroxaban, S4 pocket, Molecular dynamics simulation, Binding free energy

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