Computational investigation of amide derivative as potential anti-carbapenem-resistant Pseudomonas aeruginosa

Abstract

Recent findings indicate a surge in morbidity and mortality probabilities associated with infections caused by carbapenem-resistant strains, underscoring an urgent need for the development of effective drugs against these strains. This study employs Density Functional Theory (DFT) with the ωB97XD/6–311++G (2d, 2p) model to investigate the electronic, structural, and the biological potential of N1, N10-Bis (1,3,4-thiadiazolo (3,2-a)pyridine-2-yl)-decanediamide (TDZ). Fourier Transform Infrared Spectroscopy highlights significant assignments related to C-H, C=C, and N=H functionalities, aligning well with experimental results. Chemical reactivity analysis orders the energy gap as TDZ_Acetone > TDZ_Gas > TDZ_DMSO > TDZ_Water. The visualization of weak interaction in wider regions of steric repulsions are seen for TDZ in solvents DMSO, acetone and water as well as transformation of strong halogen bonds to van der Waals interaction. Visual findings reveal the propensity of the compound to form hydrogen bonds with protein targets due to high electron localization around hydrogen atoms. Pharmacokinetics studies indicate TDZ's favorable intestinal absorption at 50.525 %. Moreover, TDZ does not inhibit hERG 1, eliminating the risk of potassium channel blocking-induced cardiac arrhythmia. Molecular docking analysis shows TDZ's enhanced biological activity and stronger binding affinity with 5XNW, with a binding affinity of −4.5 kcal/mol and the formation of five conventional hydrogen bonds. Comparatively, for 4AKX, the standard drug Dori records eight hydrogen bond interactions at −6.8 kcal/mol, while TDZ records nine interactions at −8.6 kcal/mol. This suggests that, despite Dori's favorable interactions and good biological activity, TDZ exhibits superior binding affinity and heightened biological activity potential, positioning it as a promising drug candidate against carbapenem-resistant Pseudomonas aeruginosa infections.