Structure-guided identification of potential inhibitors of MurB from S. typhimurium LT2 strain: towards therapeutic development against multidrug resistance.

MurB or UDP-N-acetylenolpyruvoylglucosamine reductase (EC 1.3.1.98) is involved in the synthesis of bacterial cell walls of Salmonella typhimurium LT2 as it catalyzes one of the reactions in the formation of peptidoglycan. Since the enzyme is required for bacterial survival and is not present in humans, this makes it an ideal drug target, for multidrug resistance (MDR) strains. Thus, we proceeded with the identification of novel inhibitors of MurB that could overcome the existing resistance. The potential leads were identified from the PubChem library by selecting compounds with high structural similarity to the known inhibitors of MurB. These compounds were then taken through molecular docking studies and were further assessed based on physicochemical and ADMET characteristics. Regarding binding efficiency and drug-likeliness, two hit molecules with PubChem CID:10416900 and CID:14163894 were identified against MurB. Both compounds were closely bound to the MurB active site and did not induce any substantial structural changes in the MurB structure during all-atom molecular dynamics (MD) simulations and MM-PBSA studies. These compounds showed higher potential than the existing inhibitors and stood out as promising leads for the development of therapeutic inhibitors of MurB. The findings of the study, therefore, point to the viability of these compounds in the treatment of bacterial infections, thus enhancing the quality of patient care and disease management. More studies and experimental validation are required to explore their clinical use to the optimum.