Identification of secondary metabolites from Crescentia cujete as promising antibacterial therapeutics targeting type 2A topoisomerases through molecular dynamics simulation.

The potential of fluoroquinolones as remarkable antibacterial agents evolved from their ability to generate 'poison' complexes between type IIA topoisomerases [topo2As (DNA gyrases and topoisomerases IV)] and DNA. However, the overuse of fluoroquinolones coupled with chromosomal mutations in topo2As has increased incidence of resistance and consequently undermined the application of the currently available fluoroquinolones in clinical practice. In this study, the molecular mechanism of interaction between the secondary metabolites of Crescentia cujete (an underutilized plant with proven anti-bacterial activity) and topo2As was investigated using computational methods. Through molecular docking, the top five compounds with the best affinity for each topo2A were identified and subjected to molecular dynamics simulation over a period of 100 ns. The results revealed that the identified compounds had higher binding energy values than the reference standards against the topo2As except for topoisomerase IV ParC, and this was consistent with the results of the structural stability and compactness of the resulting complexes. Specifically, cistanoside D (-49.18 kcal/mol), chlorogenic acid (-55.55 kcal/mol), xylocaine (-33.08 kcal/mol), and naringenin (-35.48 kcal/mol) had the best affinity for DNA gyrase A, DNA gyrase B, topoisomerase IV ParC, and topoisomerase IV ParE, respectively. Of the constituents of C. cujete evaluated, only apigenin and luteolin had affinity for all the four targets. These observations are indicative of the identified compounds as potential inhibitors of topo2As as evidenced from the molecular interactions including hydrogen bonds established with the active site amino acids of the respective targets. This is the first in silico report on the antibacterial effect of C. cujete and the findings would guide structural modification of the identified compounds as novel inhibitors of topo2As for further in vitro and in vivo assessments.