In-silico Analysis of 1,3,4-Thiadiazol-2-yl) benzenesulfonamide Targeting SARS-CoV-2 Spike Glycoprotein and Papain-like Protease.

BACKGROUND: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, results in severe acute respiratory illness and has been declared a global public health emergency. Developing effective therapeutic strategies to control the infection remains an urgent priority. The viral spike glycoproteins and proteases play crucial roles in mediating host cell entry and facilitating viral replication. METHODS: Thiadiazole derivatives exhibit considerable antiviral activity against various RNA and DNA viruses by disrupting early stages of viral replication. In this study, we designed ten novel thiadiazole derivatives, evaluated their biological activities, and conducted molecular docking analyses targeting the SARS-CoV-2 spike glycoprotein (PDB ID: 6VSB) and papain-like protease (PDB ID: 6W9C). RESULTS: The synthesized thiadiazole derivatives were evaluated for cytotoxicity and antiviral activity against SARS-CoV-2 in Vero E6 cells. Most compounds exhibited acceptable cytotoxic profiles (CC50: 1020-1902 μM/mL), while derivatives 1d, 1g, and 1i showed moderate to weak antiviral activity with low IC50 values, indicating strong inhibition of viral replication. Molecular docking further identified molecules 1i and 1f as having high binding affinities and favourable conformational stability, warranting detailed molecular dynamics simulation studies. DISCUSSION: The docking interactions suggest that these derivatives may inhibit viral entry and replication by interacting with key viral proteins. CONCLUSION: The binding energy scores indicate that these pharmacologically active thiadiazole derivatives may have significant potential against SARS-CoV-2, positioning them as promising candidates for the development of effective antiviral agents.