Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Department of Pharmacy, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
Molecules. 2019 Oct 27;24(21):3872. doi: 10.3390/molecules24213872.
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.
吗啡、羟考酮、芬太尼和其他μ-阿片受体（MOR）激动剂已在镇痛治疗中使用了数十年。然而，这些药物与许多副作用相关，如欣快感、成瘾、呼吸抑制和胃肠道不良反应，因此，规避这些缺点非常重要。为了鉴定具有 MOR 抑制活性的新型肽配体，我们开发了一种虚拟筛选方案，包括基于受体的药效团筛选、对接研究和分子动力学模拟，该方案用于筛选内部构建的四肽配体虚拟库。对得分最高的三个化合物进行了合成和生物学评价，揭示了一个具有良好 MOR 反向激动剂作用和对δ-阿片受体选择性的命中化合物（肽 1）。这些结果证实了我们计算方法的可靠性，并为开发新的强效 MOR 调节剂提供了有希望的起点。
