Exploring the Potential of Coumarins against the Flavoenzyme DprE1 forAnti-TB Activity: Insights from Molecular Docking, In silico Druglikeness,ADMET, MD Simulations, MMGBSA, and DFT Studies

Introduction:: Tuberculosis (TB), also known as the "white death", is a highly infectious and deadly disease caused by Mycobacterium tuberculosis. This study employed highthroughput computational screening to identify potential inhibitors of DprE1. At the molecular level, DprE1 emerges as a critical player in the battle against TB. Methods:: Coumarins from the Zinc15 database were screened, and docking revealed ZINC000002148091, ZINC000002149141, ZINC000002150525, and ZINC000002151830 as top hits based on strong binding affinity against DprE1 (PDB: 4P8L). Validation was performed through re-docking, confirming the reliability of the performed protocol. Results:: The hits exhibited satisfactory druglikeness and pharmacokinetic profiles and proved nonmutagenic in the AMES test. Molecular dynamics (MD) simulations showed stable proteinligand interactions over 100 ns, with compounds consistently occupying the binding pocket, as observed in the docking study. MMGBSA analysis indicated tight binding. Density functional theory (DFT) calculations provided insight into electronic structure and reactivity. discussion: Overall, this comprehensive computational approach identified promising coumarin- based hits against DprE1, offering the potential for TB treatment. It underscores the need for further exploration through in vitro and in vivo studies to validate their efficacy and safety. conclusion: Computational analysis indicated that coumarin-based compounds can be explored for the development of potential DprE1 inhibitors. Targeting DprE1 can be an excellent strategy for the development of antitubercular compounds.