In silico screening of natural compounds as potential inhibitors against SecA protein of Acinetobacter baumannii.

SecA protein is a vital protein in bacterial protein transport systems and has been reported as a promising drug target in various bacteria, including the multidrug-resistant Acinetobacter baumannii for which development of novel drugs are urgently needed. To this end, the present study aims to screen natural compounds as potential inhibitors against SecA protein of this pathogen. Initially, structural modeling of SecA protein was performed to generate multiple models, which were assessed using various criteria. The most reliable model, Rank3 from AlphaFold2, was selected for molecular dynamics (MD) simulation study to obtain an energy-minimized structure. Virtual screening of this energy-minimized structure against the natural compound databases (LOTUS and CMNPD) identified five natural compounds, namely TCC, TMX, DDA, PF, and DOP with docking scores of - 9.801 kcal/mol, - 9.565 kcal/mol, - 9.092 kcal/mol, - 8.862 kcal/mol, and - 8.758 kcal/mol, respectively, which were significantly better than those of known SecA inhibitors CJ-21058 (- 3.92 kcal/mol), Pannomycin (- 3.234 kcal/mol), and Rose Bengal (- 2.608 kcal/mol). MD simulation studies confirmed the stability of protein-ligand complexes for all five compounds. Although DOP demonstrated the strongest binding energy (ΔG = - 46.93 ± 6.11 kcal/mol), it was excluded as it could cause respiratory toxicity and eye irritation. TMX, on the other hand, showed significant binding energy (ΔG = - 38.23 ± 2.97 kcal/mol), complex stability, good bioavailability, and an acceptable safety profile, indicating it as a potential inhibitor against SecA protein. Thus, our study uncovers a natural compound TMX as a potential inhibitor against a specific target protein. This can be further explored for experimental validation to develop novel drugs against the infectious diseases caused by A. baumannii/other related clinically important pathogens.