Screening of Novel Inhibitors Targeting the Non-ATP-binding Domain of

objective

methodsA three-dimensional structural model of S. aureus SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential.

resultsThe four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA.

conclusionIn this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of S. aureus drug resistance.