Anxiolytic-like activity of serotonin-3 receptor antagonist: In-silico molecular modeling, drug-likeness and evaluation of anxiolytic activity

Abstract

Serotonin-3 receptor antagonists have a significant impact in treating nausea and vomiting, and various diseases of the central nervous system. Patients receiving chemotherapy have anxiety as one of their complications. Therefore, we explored the anxiolytic effect of the test compound, 6d {2-[4-(prop-2-en-1-yl)piperazin-1-yl]-1,8-naphthyridine-3-carbonitrile}, and the standard 5-HT3 receptor antagonist, ondansetron. In this research, we carried out computational study to predict drug-likeness and bioactivity using online prediction tools. In-silico molecular docking studies were performed with the four conformations of 5-HT3 receptors using AutoDoc Vina software and binding interactions were analyzed using Biovia Discovery Studio. Anxiolytic studies were conducted in mice using various animal models. Both the test and standard drug satisfied Lipinski and Veber rules, showed high oral absorption and blood-brain barrier permeability. In the toxicity prediction, the test compound showed higher LD50 compared to ondansetron and did not display other toxicities, whereas ondansetron exhibited mutagenicity. Docking studies revealed that the test compound has higher binding affinity with F, I1 and T conformations and lesser binding affinity with I2 conformation compared to ondansetron. Anxiolytic evaluation disclosed that the test compound and ondansetron exhibited significant anxiolytic activity at 10 mg/kg dose compared to saline control.

Keywords

• 5-ht3 receptor antagonist
• anxiolytics
• molecular docking
• admet