ANALYSIS OF INTERACTIONS BETWEEN SARS-COV-2 MAIN PROTEASE (MPRO) AND CANDIDATE LIGANDS FOR NEW ANTIVIRAL DRUGS AGAINST COVID-19: FROM CLASSICAL MOLECULAR DYNAMICS TO QUANTUM MECHANICS

Severe acute respiratory syndrome virus (SARS-CoV-2), a single-stranded positive-RNA β-coronavirus, was responsible for the COVID-19 pandemic, which highlighted the urgency of developing new therapeutic approaches against the disease, especially in the context of viral resistance to available drugs and high mutation rates of the virus. The pharmacological repertoire against SARS-CoV-2 is still limited, but new compounds specifically targeting the viral replication cycle are being developed and tested. The SARS-CoV-2 main protease (M^Pro) is a nonstructural protein conserved among coronaviruses responsible for cleavage of the viral polyprotein and generation of mature proteins that promote its replication, which makes it an attractive target in the search for broad-spectrum anti-coronavirus inhibitors. Many candidate molecules for new drugs have been discovered by virtual screening and computer-assisted drug design techniques, which are rapid and cost-effective methods for identifying promising targets. In a previous work, the group performed a structure-based virtual screening of the Enamine database with approximately 6 billion molecules. The ligands were anchored in the catalytic site of M^Pro by the molecular docking technique. Those that bound with higher affinity and lower Gibbs free energy of binding were selected for in silico predictions of pharmacokinetic properties, which evaluated parameters of oral bioavailability based on Lipinski's rules, permeability, solubility, substrate of cytochrome P450 enzymes, acute toxicity, hepatotoxicity, cardiotoxicity, mutagenicity and respiratory sensitization. Of the 102 ligands that passed the pharmacokinetic screening, 11 met all the desired pharmacokinetic criteria. In this context, the objective of this work is to perform classical molecular dynamics simulations of M^Pro in complex with these 11 ligands to validate their interaction properties and potential protease inhibition, calculate the stability and mean fluctuation (RMSF) of the ligand in the active site of M^Pro and characterize the protein-ligand interaction. Furthermore, calculate the Fukui reactivity indices for M^Pro and each ligand in order to elucidate their electrophilic and nucleophilic properties in terms of molecular orbitals to, if necessary, propose structural optimizations to increase the inhibition efficacy and minimize unwanted side effects.