Pyrrolothiazolones as Potential Inhibitors for the nsP2B‐nsP3 Protease of Dengue Virus and Their Mechanism of Synthesis. Issue 32 (27th August 2019) - Vishvakarma, Vijay Kumar
Abstract: Dengue fever is a severe disease in the present time. Based on literature, there is no effective approved medicine available in the market for the treatment of dengue fever. This fever is spreading rapidly and there is an urgency to find the potential and cost‐effective antiviral compounds for the development of medicine to cure the patients from dengue fever. Different computational and experimental approaches have been tried to find the potential inhibitors for the nsP2B‐nsP3 protease of dengue virus. In the present work, a four component one‐pot reaction was designed to get pyrrolothiazolones & its mechanism of synthesis was studied by density functional theory. A library based on pyrrolothiazolones was created using computational tools. Further, the designed compounds were docked to get the potent inhibitor aginst the nsP2B‐nsP3 protease of dengue virus. Further, different parameters like absorption, distribution, metabolism, excretion and toxicity were applied. DFT analysis of the hit compounds were performed using Gaussian 09. The molecular dynamics simulations study was performed to check the formation of complex between the screened compound and nsP2B‐nsP3 protease of dengue virus. Finally, the molecular mechanics‐Poisson Boltzmann surface area analysis was performed to determine the effective binding for the formation of complex of potent compound with the nsP2B‐nsP3 protease of dengue virus. Abstract : This works is focussed to develop a theoretical model to develop potential inhibitors against nsP2B‐nsP3 protease of dengue virus. Therefore, one pot synthesis was designed to get pyrrolothiazolones & it's synthesis was studied through DFT. CMPD 209 showed the best inhibition of nsP2B‐nsP3 protease of DENV based on the docking score and physiochemical properties. Further, molecular dynamics simulations of nsP2B‐nsP3 protease of with and without CMPD 209 was investigated and the binding energy was evaluated using MM‐PBSA.