Computer-aided drug discovery of potential semisynthetic inhibitors for SARS-CoV-2 main protease: A multi-phase computational approach

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) is a key target for drug development in the fight against COVID-19 and computer-aided drug design (CADD) offers a promising way to discover potential drugs. Aim: Building on our team’s previous efforts against COVID-19, we have carefully curated a set of 80 semi-synthetic compounds. These compounds were selected matching the key pharmacophoric features of SARS-CoV-2 Mpro inhibitors. Objective: The aim of this study is to identify the most effective inhibitors of SARS-CoV-2 Mpro using a CAAD approach. Method: We employed a comprehensive approach, subjecting the selected compounds to molecular docking against Mpro (PDB ID: 6LU7). We then conducted thorough absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluations and toxicity assessments to determine the drug-likeness of the selected compounds. Further substantiation was provided by meticulous density functional theory (DFT) investigations and molecular dynamics (MD) simulations at 150 nanoseconds to study the electronic properties and stability of the complexes formed by the most promising candidates. Result: Molecular docking analysis revealed favorable binding modes and robust free energy profiles for compounds 12, 15, 17, 40, 47, 67, and 70. DFT investigations indicated that compounds 12, 15, 67, and 70 have a heightened potential to form efficient binding interactions with Mpro. MD simulations (150 ns) of compounds 67 and 70 showed stable binding within the Mpro active site, with average ligand root mean square deviation (RMSD) values of 7.5 Å (67) and 4.4 Å (70), and a consistent center-of-mass distance (~21.7 Å). Molecular mechanics-generalized born surface area (MM-GBSA) calculations revealed average binding free energies of −25.92 kcal/mol and −30.62 kcal/mol for compounds 67 and 70, respectively, indicating strong and favorable interactions in both cases. Conclusion: Our study designates compounds 67 and 70 as promising candidates for effective Mpro inhibition, with strong potential for future experimental studies.