Signaling bias of the selected mu-opioid receptor agonists – behavioral and molecular modeling studies
Numerous research campaigns are currently carried out with the aim to find new analgesics. Classical opioid drugs are commonly used in the pain management; however, the opioid-based treatment (especially when being long-term) is related to the wide range of side effects .
Recent studies suggest that analgesic and side effects are mediated by activation of distinct signaling pathways (G protein and beta-arrestin, respectively). In this study, we confronted the outcome of behavioral studies on selected G protein-biased opioid receptor agonists (SR-14968, SR-17018, PZM21) and morphine with results of molecular modeling experiments (docking and molecular dynamics simulations carried out for both activated and inactivated receptor forms). The molecular modeling study did reveal some amino acids, interaction with which may be related to the particular behavior of SR-agonists in comparison to PZM21 and morphine.There was also a clear evidence that the stability of compound pose in the binding site of the receptor may play a role in the observed compound activity .
The study was funded by the grant 2018/31/B/NZ7/03954 financed by the National Science Centre, Poland (www.ncn.gov.pl).
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