Discovery of a novel MurA inhibitor via AlphaFold 3 model-based virtual screening

Abstract

S. aureus is one of the most important bacteria associated with human diseases. UDP-N-acetylglucosamine 1-carboxyethylene transferase (MurA) is an important enzyme involved in the synthesis of peptidoglycan in bacterial cell walls. The crystal structure of MurA from S. aureus has not been published. In this study, we used AlphaFold 3 to predict the structure of the MurA protein derived from S. aureus . The MurA-UNAG complex structure model from S. aureus was constructed through prediction of the active site and molecular docking. Molecular dynamics simulation was performed to refine and optimize the MurA–UNAG complex structure model obtained from molecular docking. This optimized structure was used for virtual screening. We identified compound X14 (4-chloro-3- (5- (2,4-dioxo-3- (2-oxo-2- (o-toluidine) ethyl) thiazolidine-5-ylidene) methyl) uran-2-ylbenzoic acid) as a MurA inhibitior (IC 50 = 20.41 ± 1.10 µM) via molecular docking, MMGBSA and the MurA inhibition activity assay. Notably, we confirmed that compound X14 has significant structural differences from known MurA inhibitors and represents a novel MurA inhibitor through the Tanimoto coefficient. The molecular dynamics simulation revealed a possible binding mode between compound X14 and MurA. In addition, our research also indicated that compound X14 has good safety for human cells (HepG2, IC 50 > 100 µM). In summary, this study not only constructed the MurA–UNAG complex structure model, but also used it for virtual screening and discovered a new MurA. These studies provide new ideas and methods for the development of drugs.