Identification of Inhibitors for Flagellar Assembly Protein FliN of Uropathogenic Escherichia coli using Virtual Screening and Molecular Dynamics Simulation Study

Escherichia coli (E. coli) is a gram-negative bacterial pathogen that poses a significant clinical and epidemiologic challenge. The selection pressure brought by the insufficient use of antibiotics has resulted in the emergence of multi-drug-resistant E. coli in the past ten years. Computational and bioinformatics methods for screening inhibitors have significantly contributed to discovering novel antibacterial agents. One possible target for novel anti-virulence drugs is motility. Motility inhibitors are generally effective at concentrations lower than those required for the antibacterial properties of traditional antibiotics, and they are likely to exert less selective pressure than current medicines. Motility may be essential for bacteria to survive, find nutrients, and escape unfavorable environments and biofilm formation. The FliN is a protein forming the bulk of the C ring of the flagella and is present in multiple copies (more than 100) in bacteria. Its absence in mammals makes it an attractive drug target for drug discovery. Two-thousand seven hundred seventy-eight natural compounds from the ZINC library were screened against FliN (PDB ID: 4YXB) using PyRx AutoDock Vina, and the top compounds were selected for secondary screening after sorting the results based on their binding energy. Based on interactional analysis, binding energy (− 7.78 kcal/mol), and inhibition constant (1.98 µM), ZINC000000619481 was the best inhibitor. This compound binds exactly as per the defined active site residues of the receptor protein. Also, molecular dynamics was performed. The eigenvalue of the selected complex was 1.241657e−05. There were no ADME properties outside of the specified range for the identified hit; it fitted exactly to the binding site of the FliN receptor well and was found to be stable in MD simulation studies. Further in vitro and in vivo studies are needed to confirm its anti-bacterial activity and use as a potential antimicrobial drug against urinary tract infections caused by E. coli.