Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides Through Structure-Based Virtual Screening

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Nov 14

PMID 31717871

Citations 11

Authors

Giulio Poli

Marilisa Pia Dimmito

Adriano Mollica

Gokhan Zengin

Sandor Benyhe

Ferenc Zador

Azzurra Stefanucci

Affiliations

Soon will be listed here.

Abstract

Morphine, oxycodone, fentanyl, and other µ-opioid receptors (MOR) agonists have been used for decades in antinociceptive therapies. However, these drugs are associated with numerous side effects, such as euphoria, addiction, respiratory depression, and adverse gastrointestinal reactions, thus, circumventing these drawbacks is of extensive importance. With the aim of identifying novel peptide ligands endowed with MOR inhibitory activity, we developed a virtual screening protocol, including receptor-based pharmacophore screening, docking studies, and molecular dynamics simulations, which was used to filter an in-house built virtual library of tetrapeptide ligands. The three top-scored compounds were synthesized and subjected to biological evaluation, revealing the identity of a hit compound (peptide 1) endowed with appreciable MOR inverse agonist effect and selectivity over δ-opioid receptors. These results confirmed the reliability of our computational approach and provided a promising starting point for the development of new potent MOR modulators.

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