Exploring the effectiveness of SARS-CoV-2 3CLpro inhibitors through molecular dynamics and binding free energy simulations

Abstract In December 2019, in the city of Wuhan in China, a novel Coronavirus was identified as the causative agent of a Severe Acute Respiratory Syndrome, later called Corona Virus Disease 2019 (COVID-19). Since the identification of the agent and sequencing of its genome, proteases such as 3CLpro and PLprothat participate in the viral cycle have been identified as possible pharmacological targets. This study aimed to evaluate the affinity of SARS-CoV-2 3CLpro (PDB 6LU7) concerning promising binders identified by other studies using virtual screening against the ZINC database and other molecules within the possibility of inhibiting the protease, such as Hydroxychloroquine, Chloroquine, and Remdesivir. Around 1,140 ns of molecular dynamics simulations were performed to evaluate stability and binding free energy values of protein-ligand complexes (60 ns for each ligand). The estimated affinity, based on 5000 frames trajectories, revealed that N3, 11b, remdesivir and a ZINC database ligand are the most promising inhibitors of 3CLpro.Given that most studies present energy results based on docking runs and one-frame coordinates analyses, the results found may present a more accurate energy value and may help experimental approaches to developing a drug against COVID-19. Despite the importance of vaccine development, alternative strategies, such as specific viral inhibitors, are important to reduce the impact of the disease on people.