Identification of novel fructose 1,6-bisphosphate aldolase inhibitors against tuberculosis: QSAR, molecular docking, and molecular dynamics simulation-based analysis of DrugBank compounds

• Published in: Journal of biomolecular structure & dynamics 2024-12, p.1
• Main Authors: Raju, Subathra, Murugan, Kasi, Nand, Mahesha, Mathpal, Shalini, Chandra, Subhash, Ramakrishnan, Muthannan Andavar, Maiti, Priyanka
• Format: Article
• Language: English
• ISSN: 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2024.2436552

Global initiatives aim to curb tuberculosis (TB) by developing efficient vaccines and drugs against Mycobacterium tuberculosis (M. tb). The pressing need for innovative and swift anti-TB drug screening methods, due to the drawbacks of traditional approaches, is met by employing Structure-based virtual screening (SBVS) and machine learning (ML) in drug discovery. The present study utilizes these methods to repurpose compounds from the DrugBank database (DBD) as anti-TB drugs, explicitly targeting the enzyme fructose-1,6-bisphosphate aldolase (FBA) in glycolysis and gluconeogenesis pathways.Five classifiers, including REPTree, Decision Stump, Random Tree, Random Forest, and J48evaluate training data against M. tbFBA. AdmetSAR 2.0 assesses drug-like properties and toxicity of ML-identified compounds using four filters. Out of 9213 DBD compounds, 5280 were predicted as TB-active. REPTree, chosen for further screening, led to the identification of four promising preclinical anti-TB drug candidates from DrugBank-Serdemetan, Parecoxib, N, N-Diethyl-2-[(2-Thienylcarbonyl) amino], and Visnadine.All screened ligands show stable binding behaviour during a 200-ns molecular dynamics simulation. Density functional theory (DFT) analysis was also employed for the analysis HOMO (highest occupied molecular orbital)/LUMO (lowest unoccupied molecular orbital) gap, and both screened hits showed efficient results. This study presents a potential avenue for effective TB therapeutics development from compounds with proven druggability in other contexts.