In-silico Screening of Novel Diterpene Derivatives for their Inhibitory Potentials against MurA Enzyme of Uropathogenic Escherichia coli

Abstract

Enzyme UDP-NAG enolpyruvyl transferase (MurA), which aids in the formation of cell walls and is identified as the primary target of the antibiotic Fosfomycin, is a significant pharmacological target in the case of uropathogenic Escherichia coli (UPEC). Finding a potent drug with a distinct mode of action is required since UPEC treatment is challenging due to resistance and resurrection. Here we have used virtual high-throughput screening and molecular dynamics simulation approach to explore the effectiveness of selected novel Diterpene derivatives against the therapeutic target MurA (both wild type and Cys115Asp mutant, which is responsible for lower effectiveness of Fosfomycin). The investigation showed improved binding efficacy of the ligands around the primary active site residue Cys115 as well as enhanced activity against Cys115Asp mutant. Against wildtype receptors, the docking score of best-docked diterpene derivative, DIT1 (-26.18) was found to be much better than that of the known drug, Fosfomycin (-23.72). There were 7 nos of hydrogen bonds formed by DIT1 and 5 nos by Fosfomycin, indicating a stronger interaction of DIT1 with MurA. The mutant form also showed similar findings, suggesting that DIT1 is much more effective than Fosfomycin. The above result justifies the potential of Diterpene derivatives in blocking the MurA active site that can prevent peptidoglycan biosynthesis. Effectiveness of DIT1 against wild type as well as Cys115Asp mutant justifies that the selected ligands can be used as suitable drug candidates against MurA to add new molecules in the treatment pipeline. This establishes innovative frameworks for the creation of strong drugs that target MurA after suitable in-vitro and in-vivo trials.