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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.
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.
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