Selective Targeting of SARS-CoV-2 Mpro with Novel Ebsulfur-Based Compounds: A Computational Drug Discovery Approach Combining Molecular Dynamics and DFT Simulations

The viral main protease (Mpro) is essential for the replication process of SARS-CoV-2, the causative agent of COVID-19. Experimental studies have shown that Ebselen, despite its broad suppression of cysteine residues beyond the active site, is more effective than N3 in inhibiting SARS-CoV-2 due to its superior targeting of Mpro. Our study focused on designing compounds with an Ebsulfur core (BIT), a potent derivative of Ebselen, to selectively occupy Mpro’s active site. By utilizing computer-aided drug discovery methods, we provided a detailed atomic-level description of the enzyme-inhibitor complex, assessing the selectivity and ADMET properties of these compounds. Among the compounds studied, b3 stood out by demonstrating pivotal interactions with subsites S1, S1[Formula: see text] and mutation-resistant cold spot residues, while maintaining a balance between ADMET properties and biological activity. Distance density analysis further revealed that b3 had the shortest distances and highest density among the other compounds, positioning it as the most suitable for proton transfer and nucleophilic attack mechanisms. To confirm the achievements of the MD simulations, DFT approach was employed to evaluate the reactivity of the proposed ligand, showing that b3 possesses the highest level of reactivity. With its robust interactions and promising pharmacokinetic profile, b3 emerges as a leading candidate for developing potent anti-SARS-CoV-2 therapies.