Structural insights into PKS13 Thioesterase inhibitors targeting Mycobacterium tuberculosis for drug-resistant tuberculosis therapy: Identification, stability assessment, and pharmacophore modeling

Mycobacterium tuberculosis is the causative agent of tuberculosis, which remains a challenge in health worldwide due to the increase in strains resistant to most of the drugs used in its treatment. The study targeted a novel therapeutic target: the thioesterase domain of Polyketide Synthase 13, a key enzyme in mycolic acid biosynthesis. Using an 85 % structural similarity cutoff, 456 compounds were identified through a PubChem similarity search against the reference ligand JS9 (PubChem CID: 171362238). Three compounds (PubChem CIDs 92,074,896, 123,910,328, and 148,817,792) were shortlisted for detailed analysis following the virtual screening. Computational analyses using re-docking, MD simulation, MMGBSA binding energy calculation, and FEL analysis were done to assess the compounds' potential and binding stability. Among the compounds, 92,074,896 had the highest stability with the most favorable binding free energy of −93.41 ± 9.96 kcal/mol, presenting consistent hydrogen bonding and minimal conformational fluctuation. Compound 123,910,328 showed moderate flexibility with strong binding affinity, while 148,817,792 was adaptable though highly flexible. RMSF, radius of gyration, and FEL analyses further established stability and adaptability within the binding pocket. Pharmacophore modeling revealed a key AARR feature (two aromatic rings and two hydrogen bond acceptors) critical for effective ligand binding, highlighting the structural requirements for interaction with the Pks13 TE domain. These compounds represent promising lead compounds for further experimental validation and underscores the importance of pharmacophore modeling in guiding anti-TB drug discovery. • Targeted Pks13 TE domain for novel anti-TB drug development. • 456 compounds screened; 3 shortlisted via virtual screening. • Compound 92,074,896 showed best stability and binding energy. • AARR pharmacophore key for effective Pks13 TE binding. • Identified leads offer promise for anti-TB drug discovery.