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OA

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.