RESUMO
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.
RESUMO
Emerging and/or re-emerging viral diseases such as dengue and Zika are a worldwide concern. Therefore, new antiviral therapeutics are necessary. In this sense, a non-structural protein with methyltransferase (MTase) activity is an attractive drug target because it plays a crucial role in dengue and Zika virus replication. Different drug strategies such as virtual screening, molecular docking, and molecular dynamics have identified new inhibitors that bind on the MTase active site. Therefore, in this review, we analyze MTase inhibitors, including S-adenosyl-L-methionine (SAM), S-adenosyl-l-homocysteine (SAH) and guanosine-5'-triphosphate (GTP) analogs, nitrogen-containing heterocycles (pyrimidine, adenosine, and pyridine), urea derivatives, and natural products. Advances in the design of MTase inhibitors could lead to the optimization of a possible single or broad-spectrum antiviral drug against dengue and Zika virus.