A Mechanistic Probe into the Dual Inhibition of T. cruzi Glucokinase and Hexokinase in Chagas Disease Treatment – A Stone Killing Two Birds?

Glucokinase (GLK) and Hexokinase (HK) have been characterized as essential targets in Trypanosoma cruzi (Tc)‐mediated infection. A recent study reported the propensity of the concomitant inhibition of TcGLK and TcHK by compounds GLK2‐003 and GLK2‐004, thereby presenting an efficient approach in Chag...

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Bibliographic Details
Published in:Chemistry & biodiversity 2021-02, Vol.18 (2), p.e2000863-n/a
Main Authors: Omolabi, Kehinde F., Odeniran, Paul O., Olotu, Fisayo A., S. Soliman, Mahmoud E.
Format: Article
Language:English
Subjects:
ADMET compliance
Binding sites
bioactive compounds
Chagas disease
Disease control
Glucokinase
Hexokinase
Homology
Medical treatment
molecular dynamics simulation
Nucleotide sequence
Perturbation
Pharmacokinetics
Protein structure
Proteins
Secondary structure
thermodynamics calculation
Trypanosoma cruzi
Vector-borne diseases
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Summary:Glucokinase (GLK) and Hexokinase (HK) have been characterized as essential targets in Trypanosoma cruzi (Tc)‐mediated infection. A recent study reported the propensity of the concomitant inhibition of TcGLK and TcHK by compounds GLK2‐003 and GLK2‐004, thereby presenting an efficient approach in Chagas disease treatment. We investigated this possibility using atomic and molecular scaling methods. Sequence alignment of TcGLK and TcHK revealed that both proteins shared approximately 33.3 % homology in their glucose/inhibitor binding sites. The total binding free energies of GLK2‐003 and GLK2‐004 were favorable in both proteins. PRO92 and THR185 were pivotal to the binding and stabilization of the ligands in TcGLK, likewise their conserved counterparts, PRO163 and THR237 in TcHK. Both compounds also induced a similar pattern of perturbations in both TcGLK and TcHK secondary structure. Findings from this study therefore provide insights into the underlying mechanisms of dual inhibition exhibited by the compounds. These results can pave way to discover and optimize novel dual Tc inhibitors with favorable pharmacokinetics properties eventuating in the mitigation of Chagas disease.
ISSN:1612-1872
1612-1880
DOI:10.1002/cbdv.202000863