Combination of Docking-Based and Pharmacophore-Based Virtual Screening Identifies Novel Agonists That Target the Urotensin Receptor

Abstract

The urotensin receptor (UT receptor), a G-protein-coupled receptor mediating urotensin-II and urotensin-II-related peptide signaling in the urotensinergic system, has multiple pharmacological activities. However, there is no drug targeting the UT receptor currently in clinical use, and the discovery of new leads is still important. The complete crystal structure of the UT receptor has not yet been resolved and a screening strategy combining multiple methods can improve the accuracy and efficiency of drug screening. This study aimed to identify novel UT receptor agonists using a combination of docking-based, pharmacophore-based, and cell-based drug screening. First, the three-dimensional structures of the UT receptor were constructed through single-template, multi-template homologous modeling and threading strategies. After structure evaluation and ligand enrichment analysis, a model from the threading modeling was selected for docking-based virtual screening based on stepwise filtering, and 1368 positive compounds were obtained from our compound library. Second, the pharmacophore models were constructed using known ligands targeting the UT receptor for pharmacophore-based virtual screening. A model was selected after model validation, and 300 positive compounds were retrieved. Then, after intersecting the results of two different virtual screening methods with 570 compound entities from our primary screening, 14 compounds were obtained. Finally, three hits were obtained after in vitro confirmation. Furthermore, preliminary evaluation of the hits showed that they influenced glucose consumption. In summary, by integrating docking-based, pharmacophore-based, and in vitro drug screening, three new agonists targeting the UT receptor were identified which may serve as promising therapeutic agents for urotensinergic system disorders.