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

Poli, Giulio and Dimmito, Marilisa Pia and Mollica, Adriano and Zengin, Gokhan and Benyhe, Sándor and Zádor, Ferenc and Stefanucci, Azzurra (2019) Discovery of Novel mu-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening. MOLECULES, 24 (21). No.-3872. ISSN 1420-3049

Preview

Text molecules-24-03872-v2.pdf Download (2MB) | Preview

Abstract

Morphine, oxycodone, fentanyl, and other mu-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 delta-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.

Actions (login required)

Edit Item