Design, pharmacokinetic profiling, and assessment of kinetic and thermodynamic stability of novel anti-Salmonella typhi imidazole analogues

摘要

Abstract Background Typhoid fever, a disease caused by a gram negative bacterial species known as Salmonella typhi, constitutes a significant cause of morbidity and mortality, especially in developing nations of the world. Antibiotic therapy is the major treatment option currently but the rising incidences of resistance to existing antibiotics has necessitated the search for newer ones. The aim of this study is to apply in silico techniques to design highly potent novel imidazole-based drug candidates that strongly antagonize a cell invasion protein (SipA) of Salmonella typhi.Methods In this study, a set of anti-Salmonella typhi imidazole analogues were subjected to molecular docking against an important cell invasion protein of the bacterium known as SipA using PyRx graphical user interface of AutoDock Vina software. The best ligand was selected as template for designing more potent analogues. Drug-likeness, pharmacokinetic and toxicity profiles of the designed ligands were assessed through the use of Swiss ADME online tool and Osiris DataWarrior V5.5.0 chemo-informatics program. Kinetic and thermodynamic stabilities of the ligands were ascertained via Density Functional Theory’s Becke-3-parameter Lee–Yang–Parr hybrid functional and 6-31G** basis set-based quantum chemical calculations.Results The bioactive ligands were found to possess Gibb’s free binding energy (ΔG) values ranging from − 5.4 to − 6.7 kcal/mol against the active sites of the protease. Ligand 13 with ΔG = − 6.7 kcal/mol was used as template to design more potent analogues; B-1 and B-2 with ΔG value of − 7.8 kcal/mol and − 7.6 kcal/mol, respectively, against the protein target. When compared with ciprofloxacin used as control with ΔG value of − 6.8 kcal/mol, the designed ligands were found to be more potent. Furthermore, drug-likeness and ADMET profiling of the designed ligands revealed that they have excellent oral bioavailability and sound pharmacokinetic profiles. In addition, quantum chemical calculations revealed HOMO–LUMO energy gap of 3.58 eV and 3.45 eV; and global electrophilicity index of 4.95 eV and 4.79 eV for B-1 and B-2 ligands, respectively, indicative of their favorable kinetic and thermodynamic stabilities.Conclusions It is envisaged that the findings of this study would provide an excellent blueprint for developing novel antibiotics against multidrug resistant Salmonella typhi.