Computational Screening of Potential Fatty Acid Synthase Inhibitors as Broad-Spectrum Antiviral Agents

Abstract

Infectious diseases caused by viruses are one of the major diseases that seriously endanger global health. The development of broad-spectrum antiviral drugs for effective control of emerging and recurrent viral infectious diseases is urgently needed. Fatty acid synthase (FAS) has been reported as a valuable target for developing broad-spectrum antiviral drugs. In this study, we aimed to screen potent FAS inhibitors as broad-spectrum antiviral agents through computational approach. A pharmacophore model was generated with crystal structure of FAS in complex with Orlistat using Pharmit server, and 2,215 compounds were screened from ZINC15 database against the pharmacophore model. Next, 12 compounds exhibited more affinity to FAS than the control compound (Orlistat) were screened using molecular docking. The top three compounds (ZINC6146291, ZINC8925941 and ZINC3257427), which showed docking affinity to FAS with −8.19 kcal/mol, −8.14 kcal/mol and −8.07 kcal/mol, respectively, were subjected to 200 ns molecular dynamics simulation to evaluate the stability of docked complexes and their interaction mechanisms. The simulation trajectory analysis showed the stable conformation observed in FAS bound of the compounds and the screened compounds were firmly bound of the active sites of FAS throughout molecular dynamics simulation. The screened FAS candidate inhibitors can be used as broad-spectrum antiviral agents for in vitro-in vivo evaluations.