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Stereoselective recognition of morphine enantiomers by -opioid receptor. | LitMetric

Stereoselective recognition of morphine enantiomers by -opioid receptor.

Natl Sci Rev

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

Published: March 2024

AI Article Synopsis

  • * Researchers used molecular dynamics simulations to study how MOR interacts with the morphine enantiomers, finding that (-)-morphine stabilizes MOR in an activated state, while (+)-morphine does not.
  • * Key amino acid residues D114 and D147 play a role in this process, underscoring that selectivity in binding involves not just affinity but also how long the receptor remains activated.

Article Abstract

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 D114 and D147, 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10896590PMC
http://dx.doi.org/10.1093/nsr/nwae029DOI Listing

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