Computational screening of benzophenone integrated derivatives (BIDs) targeting the NACHT domain of the potential target NLRP3 inflammasome

The NLRP3 inflammasome is a crucial component in the innate immune response, which regulates the caspase-1 activation for the production of proinflammatory cytokines IL-1 and IL-18. Hence, NLRP3/caspase-1/IL-β1 signaling pathway becomes responsible for the elevation of pathogenesis of several inflammatory disorders like Alzheimer's, cancer, and diabetes mellitus. Multiple molecular and cellular processes, including ionic flux, mitochondrial malfunction, reactive oxygen species generation, and lysosomal damage, have been shown to activate the NLRP3 inflammasome. We report benzophenone integrated derivative-3 (BID-3) as an effective inhibitor of NACHT domain of NLRP3 inflammasome through in silico studies, which involved molecular docking simulations, molecular dynamics simulations, binding free energy calculations as well as druglikeliness and pharmacokinetic analyses. Out of all the BIDs screened, BID-3 was predicted with higher binding efficiency, stability, and druglikeliness potential, in comparison with the MCC950 reference drug used. With the current scenario depicting no complete cure for NLRP3 inactivation, this investigation proves to be an initial breakthrough in the field of pharmacotherapy and drug-discovery. Results obtained from this study could be used as a prominent input for the in vitro and in vivo investigation of pharmacotherapeutic potential of BIDs against the above-mentioned health maladies targeting NLRP3 inflammasome.