In-silico Design of Oxadiazole Hybrids as Potential Inhibitors of Dengue Virus NS2B-NS3 Protease

This study aimed at designing highly potent dengue virus (DENV) inhibitors targeting the NS2B-NS3 protease from 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole (BTZO) hybrid through quantitative-structure-activity relationship (QSAR) and subsequently structure-based design, molecular docking, and ADMET (Adsorption-Distribution-Metabolism-Excretion Toxicity) of the designed BTZO derivatives. A QSAR model was developed to correlate the biological activity with the descriptor calculated from the BTZO hybrid using multiple linear regression. The model was validated and the information from the model was used to design more potent derivatives which were evaluated through molecular docking and ADMET prediction. The QSAR model showed good statistical quality (R2Training = 0.89228, R2predicted = 0.72734 R2adjusted = 0.87074, Q2LOO = 0.81896, and cR2p = 0.8154) leading to the design of nine active BTZO derivatives with better inhibitory activity than the lead compound (7n). A binding score of -23.731, -20.210, -23.568 kcal/mol better than Panduratin and Ribavirin (-14.1715, -17.2571 kcal/mol) for compounds C-148, C-205, and C-206 respectively were obtained, including good ADMET properties. This discovery not only aided in understanding the binding manner of BTZO hybrid to the NS2B-N3 targets but also provided information for the development of active NS2B-N3 protease inhibitors.