基于虚拟筛选和分子动力学模拟的PD-1/PD-L1小分子抑制剂的发现

Discovery of PD⁃1/PD⁃L1 small molecule inhibitors based on virtual screening and molecular dynamics simulations

目的 发现具有新型结构的PD-1/PD-L1小分子抑制剂,并测试其对PD-1/PD-L1蛋白的阻断活性,为后续相关研究提供参考。方法 利用AutoDock Vina对TCM和TargetMol两种天然产物分子库进行虚拟筛选,获得打分较高的分子,采用HTRF方法测试所得化合物的体外抑制活性,并通过分子动力学模拟对其稳定性和结合模式进行分析。结果与结论最终确定了一种能够与PD-L1相互作用的新型化合物754792,并证明其可以有效阻断PD-1/PD-L1与配体的结合。该研究为开发免疫检查点抑制剂提供了重要的理论依据,为进一步开发高效的PD-1/PD-L1小分子抑制剂奠定了基础。

PD⁃1/PD⁃L1 is an important pathway for tumor immunotherapy,and the study of small molecule inhibitors targeting PD⁃L1 has become a hot topic of current research.In this study,a virtual screening of the TCM database and Target mol natural product library using AutoDock Vina was performed,and five hits molecules with high scoring were obtained,their stability and binding modes were also analyzed by molecular mechanics simulations.A new compound 754792,capable of interacting with PD⁃L1,was finally identified and its effective blocking of PD⁃1/PD⁃L1 binding function was demonstrated.This study provides an important theoretical basis for the development of immune checkpoint inhibitors and makes a foundation for further development of PD⁃1/PD⁃L1 small molecule inhibitors.