In silico identification of quinoline-pyridine hybrids binding to Mycobacterium protein kinase B, assessment by molecular dynamics simulation and quantum mechanics calculation, and in vitro validation of antimicrobial activity.

Tuberculosis (TB) remains the world's deadliest infectious disease, with treatment increasingly complicated by the emergence of multidrug-resistant strains (MDR-TB). This study conducted structure-based drug screening targeting Mycobacterium tuberculosis protein kinase B (MtPknB), a serine/threonine kinase essential for M. tuberculosis survival and proliferation, to identify novel anti-TB drug candidates. From the ChemBridge library, a hierarchical screening pipeline integrating docking and molecular dynamics simulations identified candidate compounds. Among these, a quinoline-pyridine hybrid chemical demonstrated antibacterial activity against Mycobacterium smegmatis (IC = 31.8 μM) without toxicity to Escherichia coli or mammalian cells. MM-PBSA and ab initio fragment molecular orbital (FMO) analyses revealed LEU17, VAL25, and MET155 as key stabilizing residues in the MtPknB active site. ProLIF interaction fingerprinting confirmed stable hydrophobic and van der Waals interactions formed by the quinoline-pyridine hybrid chemical. SwissADME and ProTox-3.0 predictions indicated favorable drug-like properties for the quinoline-pyridine hybrid chemical, despite potential toxicity risks. Structure-activity relationship analysis of the quinoline-pyridine hybrid chemical analogs demonstrated that subtle variations in hydrophobic interactions and substituent positioning significantly influence antibacterial potency. These findings position these chemicals as promising lead compounds for MtPknB-targeted anti-TB drug development.