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Updated: Jun 29, 2025

Identification of Kinase-substrate Pairs Using High Throughput Screening

Identification of Kinase-substrate Pairs Using High Throughput Screening

Published on: August 29, 2015

Inhibitor Trapping in Kinases.

Danislav S Spassov¹, Mariyana Atanasova¹, Irini Doytchinova¹

¹Drug Design and Bioinformatics Lab, Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria.

International Journal of Molecular Sciences

|March 28, 2024

Summary

Enzyme inhibitor trapping, a mechanism where proteins bind drugs tightly, was discovered in N-myristoyltransferases (NMTs) and now also in kinases. This significantly boosts drug potency and affinity.

Keywords:

Abl Src binding affinity binding affinity prediction drug design drug potency imatinib kinases protein conformation

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Last Updated: Jun 29, 2025

Identification of Kinase-substrate Pairs Using High Throughput Screening

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Published on: August 29, 2015

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

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Published on: June 30, 2019

Area of Science:

Biochemistry
Enzymology
Pharmacology

Background:

Enzyme inhibition is crucial for drug development.
N-myristoyltransferases (NMTs) utilize a novel 'inhibitor trapping' mechanism.
The prevalence of inhibitor trapping in other enzyme families is unknown.

Purpose of the Study:

To investigate inhibitor trapping in kinases.
To determine if inhibitor trapping is exclusive to NMTs.
To explore the structural basis of inhibitor trapping in kinases.

Main Methods:

Biochemical assays to measure inhibitor binding affinity.
Structural biology techniques (e.g., X-ray crystallography) to visualize drug-protein interactions.
Mutagenesis studies to identify key residues involved in trapping.

Main Results:

Inhibitor trapping was confirmed in Abl kinase with the drug imatinib.
The p38α kinase also exhibits inhibitor trapping, influenced by a specific methyl group.
This mechanism dramatically enhances inhibitor affinity, by thousands of times.

Conclusions:

Inhibitor trapping is not limited to NMTs but also occurs in kinases.
This mechanism is a critical determinant of drug affinity and potency.
Understanding inhibitor trapping can guide the design of more effective therapeutics.