Probing Non-peptide Agonists Binding at the Human Nociceptin/orphanin FQ Receptor: a Molecular Modelling Study

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Date 2025 Jan 10

PMID 39790123

Authors

Matteo Gozzi

Davide Malfacini

Valentina Albanese

Salvatore Pacifico

Delia Preti

Remo Guerrini

Girolamo Calo

Antonella Ciancetta

Affiliations

Soon will be listed here.

Abstract

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive. In this study, by leveraging the available structural information and using N/OFQ(1-13)-NH as a reference compound, we developed a computational protocol based on docking followed by short molecular dynamics (MD) simulations that can suggest small molecule agonist binding modes at the NOP receptor that are reproducible and stable over time in the solvated membrane-embedded receptor active state and in agreement with known structure-activity relationship (SAR) data.

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