ABSTRACT
BACKGROUND: Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. OBJECTIVE: The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. METHODS: We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones. Data were further reduced using pharmacophore mapping theory. Finally, we employed molecular-simulation studies to calculate the binding affinity of the screened candidates with DNA gyrase, alongside an analysis of side effects. RESULTS: A total of 16 drug candidates from the Mantra 2.0 database were screened. The pharmacophoric features of the screened candidates were examined and nalidixic acid features compared using the PharamGist program. A total of 11 compounds with the highest pharmacophore score were considered for binding energy calculation. Finally, we analysed the side effects of the eight drug candidates that showed significant binding affinity in the simulation study. CONCLUSION: Overall, flufenamic acid and sulconazole may be potential drug candidates that could be studied in vitro to assess their resistance profile against Salmonella enterica Typhimurium.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical/methods , Drug Repositioning/methods , Drug Resistance, Bacterial/drug effects , Salmonella typhimurium/drug effects , Topoisomerase II Inhibitors/pharmacology , Anti-Bacterial Agents/metabolism , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Databases, Factual , Flufenamic Acid/metabolism , Flufenamic Acid/pharmacology , Gene Expression Regulation, Bacterial/drug effects , Imidazoles/metabolism , Imidazoles/pharmacology , Molecular Docking Simulation , Reproducibility of Results , Salmonella typhimurium/pathogenicityABSTRACT
The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases are reported that Influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. Most importantly, H274Y mutation in neuraminidase exhibits high levels of resistance to oseltamivir. In this report, a novel class of lead molecule with potential NA inhibitory activity was found from the traditional Chinese medicine database (TCMD) using virtual screening approach. Initially ADME properties of the lead compounds were analyzed with respect to the Lipinski rule of five. Subsequently, the data reduction was carried out by employing molecular docking study. Final validation was done by means of molecular dynamic simulations. The toxicity profiles for the screened compound were also analyzed. The result indicates that neoglucobrassicin (a compound derived from TCMD) become a promising lead compound and be effective in treating oseltamivir-resistant influenza virus strains.