Exploring the Potential of Vortioxetine Derivatives as Inhibitors of SARS‐CoV‐2 Main Protease: A Computational Study

Abstract

AbstractIn recent years, Vortioxetine derivatives have attracted much attention as main protease inhibitors of SARS‐CoV‐2. In this study, the structure‐activity relationship of 32 Vortioxetine derivatives was studied by CoMFA and CoMSIA models. The results show that CoMFA (q2=0.522, r2=0.996) and CoMSIA (q2=0.562, r2=0.934) have good estimation stability and prediction ability. Subsequently, through the analysis of 3D‐QSAR model, we designed four novel compounds, and verified that the pharmacokinetic properties of the new molecules were superior to compound 28 by ADMET, and verified the key amino acid action sites of the new molecule by molecular docking. Finally, the new molecules was compared with compound 28 by molecular dynamics simulation and MMPBSA, which further verified the efficacy of the new molecules, wherein the binding free energy N1 (ΔG=−161.38 kJ/mol)>N4 (ΔG=−154.19 kJ/mol)>C28 (ΔG=−129.13 kJ/mol), indicating that the newly designed drug molecules are more suitable for subsequent experimental verification. The findings presented herein can offer valuable guidance for the design and development of efficacious and innovative inhibitors targeting the SARS‐CoV‐2 main protease.