Almakfoukh, Abdonasr Mohamed Ali
(2021)
In silico analysis, molecular modeling
and docking of pseudomonas
aeruginosa putative choline kinase.
Masters thesis, Universiti Sains Malaysia.
Abstract
Pseudomonas aeruginosa is a major player in the bacterial invasion. Treating
P. aeruginosa infections has become a serious challenge due to the bacterium's ability
to survive several of the currently available medicines. To put an end to the
antimicrobial resistance (AMR) issue, the quest for novel antimicrobics has been a key
focus in the relevant research community. The AMR phenomenon has been evolving
at a breakneck pace that has not been matched by the development of new drugs. As a
result, innovative antimicrobials are urgently needed. Repurposing current
medications allows for the development of novel antimicrobials. Choline kinase
inhibitors (ChoKIs) could be one of these cutting-edge antimicrobials that puts an end
to AMR once and for all. ChoKIs, which are used as anticancer drugs in human, have
the potential to inhibit P. aeruginosa choline kinase (PaChoK). Inhibition of choline
kinase would disrupt the synthesis of lipopolysaccharide/lipoteichoic acid molecules
that are required for the bacterial cell membrane integrity. This study aims to
characterize the basic properties of PaChoK by in silico approaches and generate the
model structure of this enzyme for further molecular docking with ChoKI to assess the
potential of utilizing ChoKIs as antimicrobial agent against P. aeruginosa. Basic
bioinformatic analysis shows that PaChoK is abundant with alanine amino acids, has
copious negatively charged residues and low solubility if expressed in Escherichia
coli. Multiple amino acid sequence alignment and protein structure superimposition
revealed homology between human and P. aeruginosa choline kinases, indicating the ChoKIs previously used to inhibit human choline kinase as potential anti-PaChoK. The
model structure of PaChoK was generated and used for docking with hemicholinium-
3 (HC-3), a well known human ChoK inhibitor. The docking results showed feasible
HC-3 interaction inside the choline-binding pocket of PaChoK, which interacts with
seven pocket residues. The evidence clearly supports the ChoKIs such as
Hemicholinium-3 appropriateness as anti-PaChoK that can be further develop into
antimicrobials. Yet, experimental validation of ChoKIs interaction with and inhibition
of PaChoK is still required to search for the most potent ChoKIs that can end AMR of
P. aeruginosa.
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