Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening
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, th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/21/3872 |
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| author | Giulio Poli Marilisa Pia Dimmito Adriano Mollica Gokhan Zengin Sandor Benyhe Ferenc Zador Azzurra Stefanucci |
| author_facet | Giulio Poli Marilisa Pia Dimmito Adriano Mollica Gokhan Zengin Sandor Benyhe Ferenc Zador Azzurra Stefanucci |
| author_sort | Giulio Poli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T03:35:28Z |
| format | Article |
| id | doaj.art-feafdefcfb6f4c4bae3239398da7b8ca |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T03:35:28Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-feafdefcfb6f4c4bae3239398da7b8ca2022-12-21T19:54:53ZengMDPI AGMolecules1420-30492019-10-012421387210.3390/molecules24213872molecules24213872Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual ScreeningGiulio Poli0Marilisa Pia Dimmito1Adriano Mollica2Gokhan Zengin3Sandor Benyhe4Ferenc Zador5Azzurra Stefanucci6Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, ItalyDepartment of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, ItalyDepartment of Biology, Science Faculty, Selcuk University, 42130 Konya, TurkeyInstitute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, 6726, Szeged, HungaryInstitute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, 6726, Szeged, HungaryDepartment of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, ItalyMorphine, 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.https://www.mdpi.com/1420-3049/24/21/3872peptidesvirtual screeningμ-opioid receptorpharmacophoredocking |
| spellingShingle | Giulio Poli Marilisa Pia Dimmito Adriano Mollica Gokhan Zengin Sandor Benyhe Ferenc Zador Azzurra Stefanucci Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening Molecules peptides virtual screening μ-opioid receptor pharmacophore docking |
| title | Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening |
| title_full | Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening |
| title_fullStr | Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening |
| title_full_unstemmed | Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening |
| title_short | Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening |
| title_sort | discovery of novel µ opioid receptor inverse agonist from a combinatorial library of tetrapeptides through structure based virtual screening |
| topic | peptides virtual screening μ-opioid receptor pharmacophore docking |
| url | https://www.mdpi.com/1420-3049/24/21/3872 |
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