Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors
1School of Data Science and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United States.
ACS Pharmacology & Translational Science
|August 17, 2023
Summary
Macrocyclic kinase inhibitors (MKIs) offer improved selectivity and drug resistance potential. This study reveals their rigid scaffolds maintain similar binding modes to acyclic precursors, aiding rational MKI design.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Drug Discovery
Background:
- Macrocyclic kinase inhibitors (MKIs) show promise for selectivity and overcoming drug resistance.
- Designing novel MKIs is challenging due to their complex structures.
Purpose of the Study:
- To facilitate the rational design and discovery of MKIs.
- To investigate the structural and binding characteristics of MKIs compared to their acyclic precursors.
Main Methods:
- Performed microsecond-scale atomistic simulations for multiple MKIs.
- Constructed a comprehensive MKI database.
- Analyzed MKIs using hierarchical cluster analysis.
Main Results:
- MKI binding modes resemble those of their acyclic counterparts against kinase targets.
- MKI scaffolds exhibit rigid conformations, similar to their acyclic precursors, before and after cyclization.
- Developed a database of 641 nanomole-level MKIs across 56 human kinases.
Conclusions:
- The rigidity of MKI scaffolds is a key feature for rational design.
- The established MKI database and findings provide valuable resources for advancing MKI development.
- Understanding scaffold rigidity aids in overcoming design challenges for novel kinase inhibitors.
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