IDENTIFICATION OF ANTIBACTERIAL AGENTS AGAINST KLEBSIELLA PNEUMONIAE TARGETING THE CTX-M-15 PROTEIN USING INTEGRATED STRUCTURE MODEL-BASED VIRTUAL SCREENING METHODS

The spread of carbapenem-resistant Gram-negative bacteria, particularly those having the bla CTX-M-15 gene, has stimulated a global challenge for β-lactam antimicrobial effectiveness. This study aims to identify commercially available compounds that demonstrate strong antibacterial properties with high efficacy and low toxicity to combat the increasing problem of antibiotic resistance. Virtual screening and molecular docking techniques were employed to generate a pharmacophore model based on the molecular structure. Eleven potential compounds were selected based on their IC50 values. Subsequently, a molecular docking approach was employed to select the best three small molecules for further comprehensive investigation. Moreover, absorption, distribution, metabolism, and excretion (ADME) and toxicity analysis ensured that it can be used as a drug without the effect of health. Finally, molecular dynamic (MD) simulations and generalized Born model and solvent accessibility (MMGB/SA) were carried out to evaluate the stability of these compounds against the receptor. Three selected compounds, specifically ZINCCID (ZINC94211493, ZINC20528448, and ZINC04331046), have exhibited strong binding affinities of -8.4, -8.1, and -7.7 kcal/mol, respectively. This has been predicted as a potential competitive inhibitor targeting CTX-M-15. However, further assessment through experimental lab studies is required to evaluate the efficacy of these compounds. Initially, a structure-based model was constructed, and subsequently, molecular docking, MD simulation, ADMET analysis, and MMGB/SA were performed. Through the A-to-Z virtual screening process, the top three natural compounds were identified as potential lead molecules in the development of novel drugs targeting CTX-M-15 for combating Klebsiella infections. Keywords: Klebsiella; Structure-based; Molecular docking; Pharmacophore modeling; CTX-M-15 protein; ADMET; MMGB/SA, MD simulation.