Stereoselective recognition of morphine enantiomers by μ-opioid receptor  

作　　者：Yibo Wang Van A.Ngo Xiaohui Wang 

机构地区：[1]Laboratory of Chemical Biology,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [2]Advanced Computing for Life Sciences and Engineering Group,Science Engagement Section,National Center for Computational Sciences,Oak Ridge National Lab,Oak Ridge 37831,USA [3]School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China [4]Beijing National Laboratory for Molecular Sciences,Beijing 100190,China

出　　处：《National Science Review》2024年第3期177-185,共9页国家科学评论（英文版）

基　　金：supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0450102);the Scientific and Technological Innovation 2030(STI2030)-Major Projects(2021ZD0203000(2021ZD0203003));the National Natural Science Foundation of China(91956121,22277118 and 21950410528);the Beijing National Laboratory for Molecular Sciences(BNLMS202108);the Chinese Academy of Sciences Pioneer Hundred Talents Program.

摘　　要：Stereospecific recognition of chiral molecules plays a crucial role in biological systems.The μ-opioid receptor(MOR)exhibits binding affinity towards(-)-morphine,a well-established gold standard in pain management,while it shows minimal binding affinity for the(+)-morphine enantiomer,resulting in a lack of analgesic activity.Understanding how MOR stereoselectively recognizes morphine enantiomers has remained a puzzle in neuroscience and pharmacology for over half-a-century due to the lack of direct observation techniques.To unravel this mystery,we constructed the binding and unbinding processes of morphine enantiomers w ith MOR v ia molecular dynamics simulations to investigate the thermodynamics and kinetics governing MOR’s stereoselective recognition of morphine enantiomers.Our findings reveal that the binding of(-)-morphine stabilizes MOR in its activated state,exhibiting a deep energy well and a prolonged residence time.In contrast,(+)-morphine fails to sustain the activation state of MOR.Furthermore,the results suggest that specific residues,namely D1142.50 and D1473.32,are deprotonated in the active state of MOR bound to(-)-morphine.This work highlights that the selectivity in molecular recognition goes beyond binding affinities,extending into the realm of residence time.

关 键 词：stereoselective recognition thermodynamics and kinetics residence time morphine enantiomers μ-opioid receptor 

分 类 号：TQ241.2[化学工程—有机化工]