Discovery of novel µ-opioid receptor inverse agonist from a combinatorial library of tetrapeptides through structure-based virtual screening

Giulio Poli, Marilisa Pia Dimmito, Adriano Mollica, Gokhan Zengin, Sandor Benyhe, Ferenc Zador, Azzurra Stefanucci

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number3872
JournalMolecules
Volume24
Issue number21
DOIs
Publication statusPublished - Oct 27 2019

Keywords

  • Docking
  • Peptides
  • Pharmacophore
  • Virtual screening
  • µ-opioid receptor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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