In-silico Design of Oxadiazole Hybrids as Potential Inhibitors of Dengue Virus NS۲B-NS۳ Protease

This study aimed at designing highly potent dengue virus (DENV) inhibitors targeting the NS۲B-NS۳ protease from ۱,۲-benzisothiazol-۳(۲H)-one-۱,۳,۴-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 (R۲Training = ۰.۸۹۲۲۸, R۲predicted = ۰.۷۲۷۳۴ R۲adjusted = ۰.۸۷۰۷۴, Q۲LOO = ۰.۸۱۸۹۶, and cR۲p = ۰.۸۱۵۴) leading to the design of nine active BTZO derivatives with better inhibitory activity than the lead compound (۷n). A binding score of -۲۳.۷۳۱, -۲۰.۲۱۰, -۲۳.۵۶۸ kcal/mol better than Panduratin and Ribavirin (-۱۴.۱۷۱۵, -۱۷.۲۵۷۱ kcal/mol) for compounds C-۱۴۸, C-۲۰۵, and C-۲۰۶ respectively were obtained, including good ADMET properties. This discovery not only aided in understanding the binding manner of BTZO hybrid to the NS۲B-N۳ targets but also provided information for the development of active NS۲B-N۳ protease inhibitors.

Keywords:

ADMET , QSAR , MLR , Dengue virus , ۱ , ۲-Benzisothiazol-۳(۲H)-one