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Inhibitors of kinesin activity from structure-based computer screening
S C Hopkins1, R D Vale, I D Kuntz
1Department of Pharmaceutical Chemistry, Howard Hughes Medical Institute, University of California, San Francisco, California 94143-0446, USA. seth@itsa.ucsf.edu
Biochemistry
|March 8, 2000
Summary
Researchers identified novel small organic molecules that inhibit kinesin motor protein activity. These compounds target a specific pocket involved in microtubule binding, offering new avenues for therapeutic development.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Kinesin motor proteins are essential for intracellular transport, utilizing ATP hydrolysis.
- Inhibiting kinesin activity is a potential therapeutic strategy.
Purpose of the Study:
- To identify small organic ligands that inhibit kinesin's ATPase activity.
- To characterize the binding site and mechanism of inhibition.
Main Methods:
- Computational docking (DOCK program) of commercially available compounds.
- Assay of microtubule-stimulated ATPase activity.
- Fluorescence anisotropy and FRET for binding site localization.
Main Results:
- Identified 22 submillimolar kinesin inhibitors, falling into four chemical classes.
- Three compounds exhibited single-digit micromolar inhibition.
- Rose bengal lactone (RBL) binds to a novel pocket involving loop 8 and beta-strand 5, crucial for microtubule interaction.
Conclusions:
- A novel binding pocket in kinesin, distinct from the ATP site, has been identified for inhibitor development.
- These findings provide a basis for designing targeted kinesin inhibitors.