Abstract
Purpose: To perform a virtual screening for a set of drug-like ligand library against the Staphylococcus aureus enoyl acyl carrier protein reductase, saFabI.Methods: The virtual screening was conducted based on a previously validated pharmacophoreconstrained docking. Consequently, the top list obtained was filtered using visual inspection where forty compounds were selected for experimental testing using disk-diffusion test and broth dilution method. The hits obtained were checked for their toxicity against human fibroblasts cell lines.Results: Three compounds were active against Staphylococcus aureus and other tested gram-positive bacteria. However, no significant inhibitory activity (p < 0.05) was detected against Escherichia coli or Candida albicans. The minimum inhibitory concentration (MIC) values for the most active compounds were identified using the broth dilution method; all of them exhibited inhibitory activity within micromolar range.The docking results showed that the hits obtained exhibited a small size with a nice binding mode to saFabI enzyme, forming the important interactions with the key residues. Furthermore, the best three hits demonstrated good safety profile as they did not show any significant toxicity against human fibroblast cell line.Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents.Keywords: Enoyl acyl carrier protein reductase, saFabI, Antibacterial agents, Docking, Constraint, Virtual screening Tropical Journal of Pharmaceutical
Highlights
Enoyl acyl carrier protein reductases (ENRs) are essential enzymes for microorganisms’ survival
As for the reference ligand docking and scoring, we found the active conformation of triclosan cocrystallized with Staphylococcus aureus FabI (saFabI) in the protein data bank, PDB: 4ALL [8]
The NCI ligand library was in silico screened against the saFabI active site
Summary
Enoyl acyl carrier protein reductases (ENRs) are essential enzymes for microorganisms’ survival. These enzymes play an important role in the elongation process of synthesized fatty acids [1]. In the final step of fatty acids elongation pathway, ENRs reduce enoyl-thioester to an acyl moiety; this reduction process requires a hydride source which is provided by a bound NADH or NADPH [2]. This particular step in the fatty acid elongation pathway is shared amongst many organisms, but with significant variation in catalysing enzymes’ structure and organisation [3]. Bacterial ENRs are believed to be good specific targets for antibacterial hydrogen atoms to the protein structure and to agents development, as they will not affect the give partial charges to each atom based on the human FAS I protein [2,3]
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