EXPLORING TOPOISOMERASE AS A DRUG TARGET : MOLECULAR DOCKING ANALYSIS FOR TUBERCULOSIS DISEASE DRUG REPURPOSING

Abstract

Aim: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a leading cause of global mortality, particularly in high-burden countries. Despite decades of research, TB treatment continues to face major challenges due to the rise of multidrug-resistant strains and limitations in current therapeutic options. This study aimed to identify novel therapeutic strategies through the repurposing of FDA-approved drugs by targeting bacterial topoisomerases—essential enzymes involved in DNA replication, transcription, and cell survival. The specific objective was to use a computational approach, including molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, to screen FDA-approved compounds for their structural and functional similarity to Levofloxacin, a known topoisomerase inhibitor, and to assess their potential as anti-tubercular agents with favorable safety and efficacy profiles. Result: The molecular docking analysis was performed on a dataset of 388 FDA-approved drugs to evaluate their potential binding affinities with topoisomerase enzymes implicated in MTB survival. Out of these, 48 compounds fulfilled the required pharmacokinetic and drug-likeness xi properties, such as Lipinski’s Rule of Five, blood-brain barrier permeability, and minimal PAINS (Pan Assay Interference Compounds) alerts. Among them, 14 compounds exhibited high binding affinities with docking scores better than -8.0 kcal/mol, suggesting a strong and stable interaction with the target protein. Notably, Quarfloxacin, Finafloxacin, Ofloxacin, D-levofloxacin, and Sitafloxacin emerged as the top-performing candidates based on both docking scores and favorable ADMET profiles. These compounds demonstrated high water solubility, significant gastrointestinal absorption, and minimal predicted toxicity, including low hepatotoxicity and no major immunotoxic or carcinogenic risks. The structural interactions revealed key residues involved in ligand binding, highlighting the potential for these compounds to effectively inhibit topoisomerase activity in MTB. Conclusion: This study reinforces the potential of drug repurposing as a viable strategy to accelerate the discovery of new treatments for tuberculosis, especially in the face of increasing drug resistance. The identification of several fluoroquinolone derivatives with strong topoisomerase binding affinity and acceptable safety profiles suggests they could serve as promising candidates for further preclinical and clinical evaluation. Specifically, Quarfloxacin and Finafloxacin demonstrated optimal pharmacokinetic and toxicity profiles, making them suitable for oral administration and further investigation. By leveraging computational tools such as molecular docking and ADMET analysis, this study demonstrates a time- and cost-effective approach to identifying new therapeutic avenues. Overall, targeting bacterial topoisomerases using repurposed drugs opens a promising path toward the development of more effective TB treatments and supports future translational research in this critical area of global health.