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Open AccessArticle

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

1
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
2
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
3
Department of Biology, Science Faculty, Selcuk University, 42130 Konya, Turkey
4
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, 6726, Szeged, Hungary
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(21), 3872; https://doi.org/10.3390/molecules24213872
Received: 7 October 2019 / Revised: 24 October 2019 / Accepted: 26 October 2019 / Published: 27 October 2019
(This article belongs to the Special Issue Neuropeptides Involved in Pain Control)
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. View Full-Text
Keywords: peptides; virtual screening; μ-opioid receptor; pharmacophore; docking peptides; virtual screening; μ-opioid receptor; pharmacophore; docking
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MDPI and ACS Style

Poli, G.; Dimmito, M.P.; Mollica, A.; Zengin, G.; Benyhe, S.; Zador, F.; Stefanucci, A. Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening. Molecules 2019, 24, 3872.

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