Molecular simulation of newly designed Mannich-based ciprofloxacin derivative as the promising scaffold for E. coli dihydropteroate synthase and DNA gyrase inhibitor.

The increasing incidence of bacterial infections has led to rise in antimicrobial resistance (AMR), a significant concern in public health across the globe. Henceforth, there is an urgency to address the AMR catastrophe, including developing new antibiotics, promoting the appropriate use of existing antibiotics, and investing more in research and development. Development of potent antibiotic derivatives is the call of the day. Herein, we designed a novel series of ciprofloxacin derivatives joined with sulfa-drugs (CIS1-15) and screened them against E. coli Dihydropteroate synthase and DNA gyrase through molecular docking and molecular dynamics (MD) simulations. MD simulation displayed the dynamics stability of the top-ranked docked poses, while flexibility and low-energy conformational states of these complexes the dynamics stability of the top-ranked docked poses. In contrast, the flexibility and low-energy conformational states of these complexes were inferred using principal component analysis and free energy landscape analysis. The derivatives of CIS2, CIS3, CIS5, CIS6, CIS8 and CIS15 showed strong binding affinity against both the target receptors with retention of conformational stability during MD. Pre- and post-MD snapshots show the crucial role of Arg63, Arg1072, Gly1073, and Val71 residues in the recognition of ciprofloxacin derivatives. Our in-depth structural study advocates that CIS5 and CIS6 could effectively inhibit DNA gyrase and dihydropteroate synthase. Overall, our comprehensive computational approach employed in this study establishes a benchmark for the identification of physiologically significant small molecules against emerging drug targets to design drugs based on their structure and locating potent drug-like molecules with promise for antibacterial potential.