Investigating the Therapeutic Potential of Coumarin-Based Compounds: In Silico Toxicological Assessment, ADMET Profiling, and Molecular Docking Simulations for the Inhibition of SARS-CoV-2 Main Protease

Abstract

This study investigates the potential of coumarin derivatives as inhibitors of SARS-CoV-2, the virus responsible for COVID-19, using advanced in silico methods. A virtual library of 256 coumarin-based molecules was generated via SmiLib v2.0 by introducing diverse functional groups (OH, CN, NO₂, NH₂) to the coumarin scaffold. Pharmacokinetic and toxicity profiles were assessed using SwissADME and ProTox-II, prioritizing compounds with favorable ADMET properties. Molecular structures were optimized through Density Functional Theory (DFT) calculations (B3LYP/6-311G++(d,p)) using Gaussian 16W software. Molecular docking simulations targeting SARS-CoV-2 Main Protease (Mpro) were performed using Schrödinger Maestro (Glide module). The most active compounds, such as Com19 (IC₅₀ = 40.31 μM), demonstrated strong binding affinity and inhibitory potential. Stability and interaction dynamics of the ligand-protein complexes were validated through Molecular Dynamics (MD) simulations under simulated physiological conditions. The integrated computational approach — combining virtual screening, ADMET evaluation, quantum chemical calculations, molecular docking, and MD simulations — highlights coumarin derivatives as promising antiviral candidates against SARS-CoV-2 and offers a rational framework for future drug development efforts