期刊论文详细信息
Bulletin of the National Research Centre
Design, pharmacokinetic profiling, and assessment of kinetic and thermodynamic stability of novel anti-Salmonella typhi imidazole analogues
Research
Adamu Uzairu1  Sani Uba1  Gideon Adamu Shallangwa1  John Philip Ameji2 
[1] Department of Chemistry, Ahmadu Bello University, P.M.B. 1044, Zaria, Kaduna State, Nigeria;Department of Chemistry, Federal University Lokoja, P.M.B. 1154, Lokoja, Kogi State, Nigeria;
关键词: Kinetic stability;    Thermodynamic stability;    Salmonella typhi;    SipA;    Imidazole;   
DOI  :  10.1186/s42269-023-00983-5
 received in 2022-12-22, accepted in 2023-01-09,  发布年份 2023
来源: Springer
PDF
【 摘 要 】

BackgroundTyphoid 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.MethodsIn 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.ResultsThe 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.ConclusionsIt is envisaged that the findings of this study would provide an excellent blueprint for developing novel antibiotics against multidrug resistant Salmonella typhi.

【 授权许可】

CC BY   
© The Author(s) 2023

【 预 览 】
附件列表
Files Size Format View
RO202305111667282ZK.pdf 4707KB PDF download
41116_2022_35_Article_IEq394.gif 1KB Image download
41116_2022_35_Article_IEq395.gif 1KB Image download
12888_2022_4443_Article_IEq3.gif 1KB Image download
41116_2022_35_Article_IEq403.gif 1KB Image download
41116_2022_35_Article_IEq410.gif 1KB Image download
41116_2022_35_Article_IEq481.gif 1KB Image download
【 图 表 】

41116_2022_35_Article_IEq481.gif

41116_2022_35_Article_IEq410.gif

41116_2022_35_Article_IEq403.gif

12888_2022_4443_Article_IEq3.gif

41116_2022_35_Article_IEq395.gif

41116_2022_35_Article_IEq394.gif

【 参考文献 】
  • [1]
  • [2]
  • [3]
  • [4]
  • [5]
  • [6]
  • [7]
  • [8]
  • [9]
  • [10]
  • [11]
  • [12]
  • [13]
  • [14]
  • [15]
  • [16]
  • [17]
  • [18]
  • [19]
  • [20]
  • [21]
  • [22]
  • [23]
  • [24]
  • [25]
  • [26]
  • [27]
  • [28]
  • [29]
  • [30]
  • [31]
  • [32]
  • [33]
  • [34]
  • [35]
  • [36]
  • [37]
  • [38]
  • [39]
  • [40]
  • [41]
  • [42]
  • [43]
  • [44]
  • [45]
  • [46]
  文献评价指标  
  下载次数:5次 浏览次数:1次