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Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators

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Abstract

Targeting the mu opioid receptor (MOR) by applying orthosteric ligands is the most frequently employed method to treat opioid use disorder (OUD). Unfortunately, most of MOR orthosteric ligands produce severe side effects, mainly due to their low selectivity over other opioid receptors. In contrast, some G protein-coupled receptor allosteric modulators have been reported to exhibit high subtype selectivity and can effectively modulate the potency and/or efficacy of orthosteric ligands. Recently, NAQ and its analog NCQ were identified as novel MOR bitopic modulators. Interestingly, NAQ and NCQ were similar in structure but exhibited different efficacy profiles to the MOR. NAQ exhibited an antagonism activity to the MOR while NCQ showed a partial agonism activity to the MOR. In the present study, molecular modeling methods were applied to explore the putative molecular mechanisms of their different functional profiles to the MOR. When NAQ binding with the inactive MOR, the ‘address’ portion of NAQ interacted with the MOR allosteric site but showed no significant allosteric modulation of the efficacy of the ‘message’ portion of NAQ. However, when NCQ binding with the inactive and active MOR, the ‘address’ portion of NCQ seemed to be able to positively modulate the efficacy of the ‘message’ portion of NCQ at varying levels. Evidentially, the substituents at the 1′- and 4′-positions of the isoquinoline ring of NCQ seemed to play a critical role in the modulatory function of the ‘address’ portion of NCQ. These findings will be invaluable to develop our next generation of MOR bitopic modulators with high affinity and subtype selectivity to potentially treat OUD.

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Acknowledgements

The work was partially supported by PHS Grant DA024022 (Y. Z.), DA050311 (Y. Z.), and the VCU Center for High-Performance Computing (CHiPC). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

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  1. Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA, 23298, USA

    Huiqun Wang, Bethany A. Reinecke & Yan Zhang

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Wang, H., Reinecke, B.A. & Zhang, Y. Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators. J Comput Aided Mol Des 34, 879–895 (2020). https://doi.org/10.1007/s10822-020-00309-x

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