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Updated: May 28, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Novel allosteric sites on Ras for lead generation
Barry J Grant1, Suryani Lukman, Harrison J Hocker
1Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America. bjgrant@umich.edu
Plos One
|November 3, 2011
Summary
Researchers developed a novel computational method to find new Ras inhibitors targeting allosteric sites. This approach successfully identified compounds that inhibit Ras signaling, offering new avenues for cancer drug development.
Area of Science:
- Oncology
- Computational Biology
- Drug Discovery
Background:
- Aberrant Ras activity is implicated in numerous cancers and developmental disorders.
- Developing effective small molecule Ras inhibitors has been challenging due to limited success with conventional methods.
Purpose of the Study:
- To discover potential inhibitors for previously uncharacterized allosteric sites of Ras using a novel multi-level computational approach.
- To validate these allosteric sites as viable drug targets for Ras-related diseases.
Main Methods:
- Coupling bioinformatics analysis, molecular simulations (molecular dynamics), and ensemble docking.
- Identifying conserved allosteric coupling and novel binding pockets near Ras switch regions.
- Screening compound libraries (ZINC and NCI) for candidate binders.
Main Results:
- Molecular dynamics revealed conserved allosteric coupling between the nucleotide-binding switch region and distal areas (loop 7, helix 5).
- Bioinformatics identified novel transient binding pockets near these allosteric regions.
- Ensemble docking selected candidate inhibitors, which were validated in cell-based assays to inhibit Ras downstream signaling.
Conclusions:
- The predicted allosteric sites are viable targets for developing novel Ras inhibitors.
- This computational approach offers a promising strategy for discovering inhibitors of previously intractable targets like Ras.
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