STRUCTURE-BASED DESIGN OF NOVEL IMIDAZOQUINOLINO-CHALCONE HYBRIDS AS PROMISING LEADS FOR DprE1-TARGETED ANTITUBERCULAR THERAPY
Tuberculosis (TB) continues to pose a major global health burden, further intensified by the rising prevalenceof multidrug-resistant (MDR) Mycobacterium tuberculosis strains. This study employed an in-silico approachtoexplore the known bioactive scaffolds of Imidazoquinolines and chalcones, which were evaluated for bindingaffinity and pharmacokinetic suitability. A curated library of 97 hybrid derivatives sourced fromthe PubChemdatabase was screened against decaprenyl phosphoryl-d-ribose 2′-epimerase (DprE1) plays a crucial role inthegrowth and survival of Mycobacterium tuberculosis. Analyses of structure–activity relationships and mechanisticinsights suggest that optimizing or hybridizing scaffolds could improve antitubercular activity. Computational screening revealed high-affinity ligands exhibiting favourable pharmacokinetic profiles, indicating significant potential as lead candidates. This broadened the range of these novel molecules as DPRE1 inhibitors throughstructure-based drug design and the assessment of drug likeliness and dependable ADMET prediction utilizingavariety of bioinformatic tools, including molecular dynamics (MD) simulations, RMSD, RMSF, Rg profile, andhydrogen bond analysis, and the mechanistic feasibility of selected hit compounds as potent DprE1 inhibitors aspromising therapeutic candidates. These findings reinforce the utility of computational screening methods instreamlining the early stages of antitubercular drug development and support further experimental validationandchemical optimization of these newer molecules.
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