Lead optimization studies towards finding NS2B/NS3 protease target-specific inhibitors as potential anti-dengue drug-like compounds.

Dengue Fever is a major threatening global health issue caused by a mosquito-borne pathogen. Even though some anti-viral drugs are now available to reduce the disease severity. Still, there is a need for better drug compound to combat with dengue fever. The NS2B/NS3 protease is a major therapeutic drug target for Insilco drug discovery. Previously, we have performed a pharmacophore feature based virtual screening studies, which has led to the identification of ZINC92615064 compound as a potent NS2B/NS3 protease inhibitor and demonstrated its potential to act as anti-dengue drug-like compound using computational approaches. In this present study, the identified lead compound ZINC92615064 has been made to undergo scaffold hopping based novel library generation, and the resulted novel library of compounds has been virtually screened on to NS2B/NS3 protease towards identifying novel proprietary scaffold of compound which is acting as a potent inhibitor for the given drug target of NS2B/NS3. A total of 16,847 novels designed compounds library was generated using the scaffold hopping technology based on the structure of the lead compound ZINC92615064. Out of which, compound design no. 3718 has shown the best binding potential with a predicted IC50 value of 417.13 nM along with a permissible range of ADMET properties based on its descriptor values. This NS2B/NS3 protease in complex with compound 3718 was subjected to a rigorous molecular dynamic simulation study to further validate this complex thermodynamic stability, along with the aim to reveal the underlying molecular level interactions and potential mode of action.