Cheminformatic and in vitro Bioprospection of Capsicum Annuum L. Metabolites as DNA Gyrase B Inhibitors

Introduction: Capsicum species are known in food and trado-medicinal uses for maladies management due their rich content of phytochemicals, but with little work done on in silico bioprospection of its volatilome. Objectives: This study targeted chemometric profiling, virtual bioprospection of potential lead metabolites in 2 Capsicum annuum L. fruit variants’ (green and red) to identify lead gyrase B inhibitors (GBIs) and provide new mechanistic insights. Methods: Metabolites were profiled using Gas Chromatography-Mass Spectrometry (GC-MS), and quantitative phytochemical assays. Extracts antioxidant (DPPH, ABTS, FRAP) and antibacterial (susceptibility testing) activities were also determined. In silico [docking, pharmacokinetics, DFT] analyses were used to identify and predict chemical features of potential lead GBIs key to extracts molecular mechanism of action. Results: Mass spectral analysis identified hydrocarbons, fatty acid and other derivatives. Quantitative phytochemical analysis showed flavonoids, cardiac glycosides and alkaloids. The green C. annuum extract had better antioxidative action, while extracts of both green and red variant showed similar antimicrobial profiles against resistant bacterial pathogens. In silico highest docking scores were observed for [1-Ethyloctyl) cyclohexane (-6.6 kcal/mol)] and dibutyl phthalate (-6.4 kcal/mol). All lead GBIs had desirable pharmacokinetics in line with the Lipinski rule of 5, and chemical reactivity properties. Conclusion: In silico and in vitro methods combination provided robust metabolomic profiling. The identified lead C. annuum-based natural GBIs contribute to the bioactivity profile and molecular mechanism of action of fractions. The study provided a first-hand report on natural GBIs derivable from Capsicum fruits which could be exploited in formulations for non-food and pharmaceutical applications.