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<p>The management of tuberculosis (TB) poses a significant challenge, particularly in low- to middle-income regions, due to its high mortality rate and severity. Given the paramount importance of maintaining the structural integrity of the bacterial cell wall, alanine racemase emerges as a critical therapeutic target due to its key role in the peptidoglycan pathway and its unique absence in humans. However, the imperative to discover novel inhibitors targeting this pathway is underscored by the rise of drug-resistant TB strains. In this study, we employed a computational drug repurposing approach to predict potential alanine racemase inhibitors by screening FDA-listed drugs cataloged in DrugBank 5.1.9. Additionally, docking studies used cycloserine, a known alanine racemase inhibitor, as a reference compound. The prioritization of a potent inhibitor relied on multiple criteria, including binding affinity, intermolecular interaction patterns, MMGBSA analysis, ΔG calculations, ADMET properties, and molecular dynamics simulations to evaluate the protein-drug&#xa0;complex stability. Our comprehensive analysis identified three compounds (DB00712, DB09064, and DB05015) as potential hits, successfully passing all prioritization processes. However, DB09064 exhibited the most promising attributes among these candidates, demonstrating enhanced complex stability, binding affinity (-8.5&#xa0;kcal/mol), and significant intermolecular interactions. Furthermore, its interaction pattern and Protein-Drug&#xa0;complex&#xa0;Root Mean Square Deviation (RMSD) trajectory closely resembled cycloserine, indicating its potential in targeting alanine racemase. Therefore, DB09064 (Ciprofibrate) is predicted as a highly potential hit. With further lead optimization and experimental validation to mitigate off-target effects, it could emerge as a novel alanine racemase inhibitor, offering potential implications for combating drug-resistant TB.</p>

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Computational drug repurposing reveals potential alanine racemase inhibitors for combating drug-resistant tuberculosis

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Keerthika LakshmanaPerumal,
  • Umashankar Vetrivel

摘要

The management of tuberculosis (TB) poses a significant challenge, particularly in low- to middle-income regions, due to its high mortality rate and severity. Given the paramount importance of maintaining the structural integrity of the bacterial cell wall, alanine racemase emerges as a critical therapeutic target due to its key role in the peptidoglycan pathway and its unique absence in humans. However, the imperative to discover novel inhibitors targeting this pathway is underscored by the rise of drug-resistant TB strains. In this study, we employed a computational drug repurposing approach to predict potential alanine racemase inhibitors by screening FDA-listed drugs cataloged in DrugBank 5.1.9. Additionally, docking studies used cycloserine, a known alanine racemase inhibitor, as a reference compound. The prioritization of a potent inhibitor relied on multiple criteria, including binding affinity, intermolecular interaction patterns, MMGBSA analysis, ΔG calculations, ADMET properties, and molecular dynamics simulations to evaluate the protein-drug complex stability. Our comprehensive analysis identified three compounds (DB00712, DB09064, and DB05015) as potential hits, successfully passing all prioritization processes. However, DB09064 exhibited the most promising attributes among these candidates, demonstrating enhanced complex stability, binding affinity (-8.5 kcal/mol), and significant intermolecular interactions. Furthermore, its interaction pattern and Protein-Drug complex Root Mean Square Deviation (RMSD) trajectory closely resembled cycloserine, indicating its potential in targeting alanine racemase. Therefore, DB09064 (Ciprofibrate) is predicted as a highly potential hit. With further lead optimization and experimental validation to mitigate off-target effects, it could emerge as a novel alanine racemase inhibitor, offering potential implications for combating drug-resistant TB.