Molecular modeling and optimization of pyranoquinolinone derivatives as potential DNA gyrase inhibitors for typhoid fever treatment: A Comprehensive QSAR, molecular docking, ADMET, and molecular dynamics simulation studies

Abstract

The emergence of multidrug resistant and extensively drug resistant strains of Salmonella typhi have necessitated conscious search for newer and better medications. In this study, a dataset of twenty-four (24) bioactive pyranoquinolinones with proven in vitro anti- Salmonella typhi activities were subjected to Genetic-Function Approximation-based QSAR modeling. The model was used to design more potent analogues of pyranoquinolinone. Then, molecular docking and molecular dynamic simulations were used to investigate the binding interaction and stability of the new ligands against the binding pockets of DNA gyrase of the Gram-negative bacteria. Subsequently, ADMET properties of the ligands were studied with the aid of SwissADME and pkCSM servers. The tetra-parametric QSAR model (R 2 train = 0.854, R 2 adj = 0.801, Q 2 CV = 0.702, c R p 2 = 0.735, R 2 test = 0.761) hints the predominating influences of molecular shape, size, and connectivity on the observed anti-bacterial activities of the explored pyranoquinolinones. The optimum model was used to designed eighth drug candidates; Q1-Q8. Molecular docking simulation revealed that the ligands bind better to DNA gyrase with docking scores (∆G) that range from -8.3 to -9.1 kcal/mol when compared with Ciprofloxacin whose ∆G value against the macromolecule is -7.4 kcal/mol. The stability of the ligand/DNA gyrase complexes was confirmed by molecular dynamic simulations. Additionally, the new ligands possess sound oral bioavailability and pharmacokinetic profiles, and could serve as potential sources of pyranoquinolinone-based antibiotics against typhoid fever.