RESUMEN
COVID-19, a disease caused by SARS-CoV-2, was declared a pandemic in 2020 and created a global crisis in health systems, with more than 545 million confirmed cases and 6.33 million deaths. In this sense, this work aims to identify possible inhibitors of the SARS-CoV-2 RdRp enzyme using in silico approaches. RdRp is a crucial enzyme in the replication and assembly cycle of new viral particles and a critical pharmacological target in the treatment of COVID-19. We performed a virtual screening based on molecular docking from our in-house chemical library, which contains a diversity of 313 structures from different chemical classes. Nine compounds were selected since they showed important interactions with the active site from RdRp. Next, the ADME-Tox in silico predictions served as a filter and selected the three most promising compounds: a coumarin LMed-052, a hydantoin LMed-087, and a guanidine LMed-250. Molecular dynamics simulations revealed details such as changes in the positions of ligands and catalytic residues during the simulations compared to the complex from molecular docking studies. Binding free energy analysis was performed using the MMGBSA method, demonstrating that LMed-052 and LMed-087 have better affinities for the RdRp by energetic contributions to the stability of the complexes when compared to LMed-250. Furthermore, LMed-052 showed significant in vitro inhibition against MHV-3, decreasing 99% of viral titers. Finally, these findings are useful to guide structural modifications aiming to improve the potential of these compounds to act as inhibitors of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
RESUMEN
The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), became the highest public health crisis nowadays. Although the use of approved vaccines for emergency immunization and the reuse of FDA-approved drugs remains at the forefront, the search for new, more selective, and potent drug candidates from synthetic compounds is also a viable alternative to combat this viral disease. In this context, the present study employed a computational virtual screening approach based on molecular docking and molecular dynamics (MD) simulation to identify possible inhibitors for SARS-CoV-2 Mpro (main protease), an important molecular target required for the maturation of the various polyproteins involved in viral replication. The virtual screening approach selected four potential inhibitors against SARS-CoV-2 Mpro. In addition, MD simulation studies revealed changes in the positions of the ligands during the simulations compared to the complex obtained in the molecular docking studies, showing the benzoylguanidines LMed-110 and LMed-136 have a higher affinity for the active site compared to the other structures that tended to leave the active site. Besides, there was a better understanding of the formation and stability of the existing H-bonds in the formed complexes and the energetic contributions to the stability of the target-ligand molecular complexes. Finally, the in silico prediction of the ADME profile suggested that LMed-136 has drug-like characteristics and good pharmacokinetic properties. Therefore, from the present study, it can be suggested that these structures can inhibit SARS-CoV-2 Mpro. Nevertheless, further studies are needed in vitro assays to investigate the antiviral properties of these structures against SARS-CoV-2.