In Silico Analysis of FDA Drugs as P2X4 Modulators for the Treatment of Alcohol Use Disorder

Abstract

Recent studies have shown the potential application of ivermectins in the treatment of alcohol use disorder (AUD). Ivermectin is a positive allosteric modulator (PAM) of P2X4R and this molecule exerts its action in the transmembrane region (known as the TM region) of trimeric channel structure (the pocket formed by Asp331, Met336, Trp46, Trp50, and Tyr42). The aim of this study is to identify FDA drugs with potential PAM properties, by exploring the P2X4Rs from four organisms (Danio rerio, Mus musculus, Rattus norvegicus, and Homo sapiens). The in silico study consists of carrying out the molecular docking of 1656 FDA-approved drugs on the structure of P2X4R, using the commercially available compounds from the ZINC¹⁵ database for virtual screening. To strengthen the reliability of the results, two docking protocols were used involving the use of two programs, Autodock 4.2 and Autodock Vina. Nine FDA drugs with potential PAM properties were identified. In addition, eight molecules with potential negative allosteric modulator (NAM) action, and 13 molecules with potential allosteric modulator (AM) action were identified. The FDA drugs identified in this study with PAM, NAM, and AM action, shared in the P2X4Rs of the four organisms, can provide a guideline to proceed with research concerning new drugs for the study and treatment of AUD.

Keywords: P2X4 receptor; allosteric modulators; drug repositioning; molecular docking; molecular modeling; virtual screening.