Screening Serine/threonine and Tyrosine Kinase Inhibitors for Histidine Kinase Inhibition

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2018 May 1

PMID 29706527

Citations 11

Authors

Kaelyn E Wilke

Conrad A Fihn

Erin E Carlson

Affiliations

Soon will be listed here.

Abstract

Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.

Citing Articles

Evaluation of expanded 2-aminobenzothiazole library as inhibitors of a model histidine kinase and virulence suppressors in Pseudomonas aeruginosa.

Fihn C, Lembke H, Gaulin J, Bouchard P, Villarreal A, Penningroth M Bioorg Chem. 2024; 153:107840.

PMID: 39362083 PMC: 11614690. DOI: 10.1016/j.bioorg.2024.107840.

Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Virulence Phenotypes.

Fihn C, Lembke H, Gaulin J, Bouchard P, Villarreal A, Penningroth M bioRxiv. 2023; .

PMID: 37205454 PMC: 10187220. DOI: 10.1101/2023.05.02.539119.

Anti-Quorum Sensing Activities of Gliptins against and .

Khayat M, Abbas H, Ibrahim T, Khayyat A, Alharbi M, Darwish K Biomedicines. 2022; 10(5).

PMID: 35625906 PMC: 9138634. DOI: 10.3390/biomedicines10051169.

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery.

Ma P, Phillips-Jones M Molecules. 2021; 26(16).

PMID: 34443697 PMC: 8399564. DOI: 10.3390/molecules26165110.

Strategies to Attenuate the Competence Regulon in .

Lella M, Tal-Gan Y Pept Sci (Hoboken). 2021; 113(4).

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