中国药科大学学报2026，Vol.57Issue(3)：295-303,9.DOI:10.11665/j.issn.1000-5048.2025110601
新型冠状病毒3CL蛋白酶与其抑制剂吡脲炔酯手性异构体的结合机制研究
Study on the binding mechanism between SARS-CoV-2 3CL protease and chiral isomers of its inhibitor pyridyl-urea diyne ester
摘要
Abstract
3CL protease(3CLpro)of SARS-CoV-2 is a pivotal enzyme required in coronavirus replication and transcription.Its highly conserved structure and the absence of homologous proteins in the host make it an ideal target for broad-spectrum anti-coronavirus drug development.In this work,we systematically investigated and compared the binding modes and dynamic properties of the four stereoisomers of a pyridyl-urea diyne ester(PyDU)molecule with two chiral centers within the 3CLpro active site.Through molecular docking,MD simulations,MM/GBSA binding free-energy calculations,and DCCM analysis,all four stereoisomers were stabilized primarily by hydrophobic packing.Among them,the(R,S)isomer exhibited the best overall performance,including docking score,binding free-energy components,and key residue interactions.The(R,S)and(S,R)isomers also enhanced the cooperative motions around the binding pocket,while the(R,S)isomer f urther modulated the flexibility of domain Ⅲ,which may influence 3CLpro dimerization.Conversely,the(S,S)isomer exhibited the weakest affinity due to insufficient hydrophobic contact.By innovatively integrating chirality,binding energy and protein dynamical features,we revealed the dual role of chirality in modulating affinity and dynamic responses,which provides a theoretical basis for the chiral-guided design of coronavirus inhibitors.关键词
3CL蛋白酶/手性异构体/分子动力学模拟/疏水作用/MM/GBSA计算Key words
3CL protease/stereoisomer/molecular dynamics simulation/hydrophobic interaction/MM/GBSA calculation分类
医药卫生引用本文复制引用
方敏,吴星雨,王文彪,林琦,高雅..新型冠状病毒3CL蛋白酶与其抑制剂吡脲炔酯手性异构体的结合机制研究[J].中国药科大学学报,2026,57(3):295-303,9.基金项目
国家自然科学基金项目(No.22373065) （No.22373065）
国家重点研发计划项目(2023YFF1204903) This study is supported by the National Natural Science Foundation of China(No.22373065),and the National Key R&D Program of China(2023YFF1204903) （2023YFF1204903）
