A combination of pharmacophore modeling, molecular docking, and virtual screening for P2Y₁₂ receptor antagonists from Chinese herbs

Abstract

P2Y 12 , a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y 12 receptor is a popular drug target. After the recent resolution of the P2Y 12 receptor's crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophorebased screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y 12 receptor antagonists from traditional Chinese herbs.Résumé : Le récepteur P2Y 12 , membre de la famille des récepteurs couplés aux protéines G, est associé à des anomalies de l'agrégation plaquettaire, un trouble qui contribue à la formation de thrombus. Comme les antagonistes du récepteur P2Y 12 représentent des solutions anti-thrombus efficaces, ce récepteur constitue une cible thérapeutique privilégiée. À la suite de la récente résolution de la structure cristalline du récepteur P2Y 12 , des études de modélisation et de simulation d'amarrage du pharmacophore ont été combinées en vue de découvrir d'éventuels antagonistes naturels. Diverses approches dont le but était de valider les modèles moléculaires du pharmacophore et d'optimiser les algorithmes d'amarrage ont été utilisées. Le modèle Hypo18, généré à partir de 24 antagonistes connus, a été retenu comme la meilleure hypothèse et comprend un noyau aromatique, un accepteur de liaison hydrogène, un volume exclu et trois surfaces hydrophobes. Nous avons donc utilisé le modèle Hypo18 aux fins du criblage de la base de données de la médecine traditionnelle chinoise, la TCMD (version 2009), dans le but de trouver d'éventuels composés actifs. Cette opération a permis de dresser une liste de 121 composés dont le profil présente une possible activité pharmacologique. Puis, les résultats de criblage du pharmacophore ont été raffinés au moyen de la simulation d'amarrage moléculaire utilisée comme méthode de réticulation. Par la suite, les 20 composés présentant les meilleurs résultats d'arrimage ont été retenus. Cet article constitue une source fiable dans le processus de recherche d'antagonistes naturels du récepteur P2Y 12 à partir de plantes médicinales chinoises. [Traduit par la Rédaction] Mots-clés : antagonistes du récepteur P2Y12, modélisation du pharmacophore, amarrage, criblage virtuel, médecin...

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