首页|Stereoselective recognition of morphine enantiomers byμ-opioid receptor

Stereoselective recognition of morphine enantiomers byμ-opioid receptor

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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 with MOR via 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.

stereoselective recognitionthermodynamics and kineticsresidence timemorphine enantiomersμ-opioid receptor

Yibo Wang、Van A.Ngo、Xiaohui Wang

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Laboratory of Chemical Biology,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China

Advanced Computing for Life Sciences and Engineering Group,Science Engagement Section,National Center for Computational Sciences,Oak Ridge National Lab,Oak Ridge 37831,USA

School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China

Beijing National Laboratory for Molecular Sciences,Beijing 100190,China

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中国科学院战略规划重点项目Scientific and Technological Innovation 2030(Major Projects)国家自然科学基金国家自然科学基金国家自然科学基金Beijing National Laboratory for Molecular SciencesChinese Academy of Sciences Pioneer Hundred Talents Program

XDB04501022021ZD02030002021ZD0203003919561212227711821950410528BNLMS202108

2024

10.1093/nsr/nwae029

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年,卷(期)：2024.11(3)
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