Discovery of the Lead Molecules Targeting the First Step of the Histidine Biosynthesis Pathway of Acinetobacter baumannii .
Nabeel AhmadAnamika SinghAkshita GuptaPradeep PantTej P SinghSujata SharmaPradeep SharmaPublished in: Journal of chemical information and modeling (2022)
Acinetobacter baumannii is a multidrug-resistant, opportunistic, nosocomial pathogen for which a new line of treatments is desperately needed. We have targeted the enzyme of the first step of the histidine biosynthesis pathway, viz., ATP-phosphoribosyltransferase (ATP-PRT). The three-dimensional structure of ATP-PRT was predicted on the template of the known three-dimensional structure of ATP-PRT from Psychrobacter arcticus ( Pa ATPPRT) using a homology modeling approach. High-throughput virtual screening (HTVS) of the antibacterial library of Life Chemicals Inc., Ontario, Canada was carried out followed by molecular dynamics simulations of the top hit compounds. In silico results were then biochemically validated using surface plasmon resonance spectroscopy. We found that two compounds, namely, F0843-0019 and F0608-0626, were binding with micromolar affinities to the ATP-phosphoribosyltransferase from Acinetobacter baumannii ( Ab ATPPRT). Both of these compounds were binding in the same way as AMP in Pa ATPPRT, and the important residues of the active site, viz., Val4, Ser72, Thr76, Tyr77, Glu95, Lys134, Val136, and Tyr156, were also interacting via hydrogen bonds. The calculated binding energies of these compounds were -10.5 kcal/mol and -11.1 kcal/mol, respectively. These two compounds can be used as the potential lead molecules for designing antibacterial compounds in the future, and this information will help in drug discovery programs against Acinetobacter worldwide.
Keyphrases
- acinetobacter baumannii
- multidrug resistant
- drug resistant
- pseudomonas aeruginosa
- molecular dynamics simulations
- gram negative
- high throughput
- drug discovery
- klebsiella pneumoniae
- molecular docking
- public health
- binding protein
- cancer therapy
- dna binding
- healthcare
- protein kinase
- mass spectrometry
- single molecule
- drug delivery
- human health
- liquid chromatography
- density functional theory
- cell wall
- health information