Molecular design, molecular docking and ADMET study of cyclic sulfonamide derivatives as SARS-CoV-2 inhibitors

Abstract

\n Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to spread globally, with more than 172 million confirmed cases and 3.57 million deaths. Cyclic sulfonamide derivative was identified as a successful compound and showed anti-SARS-CoV-2 activity. In this study, the structure and activity relationships of 35 cyclic sulfonamide compound inhibitors were investigated by using three-dimensional quantitative structure-activity relationship (3D-QSAR) and holographic quantitative structure-activity relationship (HQSAR).Two models with good statistical parameters and reliable predictive ability were obtained from the same training set, including Topomer CoMFA (\n \n \n q\n 2\n \n \n \n = 0.623,\n \n \n r\n 2\n \n \n \n = 0.938,\n \n \n r\n \n p\n r\n e\n d\n \n 2\n \n \n \n = 0.893) model and HQSAR (\n \n \n q\n 2\n \n \n \n = 0.704,\n \n \n r\n 2\n \n \n \n = 0.958,\n \n \n r\n \n p\n r\n e\n d\n \n 2\n \n =\n 0.779\n \n ) model, the established models not only have good stability, but also show good external prediction ability for the test set. The contour and color code maps of the models provide a lot of useful information for determining the structural requirements affecting the activity; this information paved the way for the design of four novel cyclic sulfonamide compounds, and predicted their pIC50\n values. We explore the interaction between the newly designed molecule and SARS-CoV-2 3CLpro by molecular docking. The docking results showed that GLU166, GLN192, ALA194, and VAL186 may be the potential active residues of the SARS-CoV-2 inhibitor evaluated in this study. Finally, the oral bioavailability and toxicity of the newly designed cyclic sulfonamide compounds were evaluated and the results showed that the four newly designed cyclic sulfonamide compounds have major ADMET properties and can be used as reliable inhibitors against COVID-19. These results may provide useful insights for the design of effective SARS-CoV-2 inhibitors.\n