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J Chem Inf Model. 2018 Feb 26;58(2):464-471. doi: 10.1021/acs.jcim.7b00399. Epub 2018 Jan 31.

Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange.

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Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco , San Francisco, California 94158, United States.
Department of Biochemistry and Microbiology. University of Victoria , Victoria, BC V8W 2Y2, Canada.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
Department of Organic Chemistry, The Weizmann Institute of Science , Rehovot, 7610001, Israel.
Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.


The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to a lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-RasG12C. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent binder that modifies the inactive, GDP-bound state of K-RasG12C. Hydrogen-deuterium exchange mass spectrometry was used to probe the protein dynamics of compound binding to the switch-II pocket and subsequent destabilization of the nucleotide-binding region. SOS-mediated nucleotide exchange assays showed that, contrary to prior switch-II pocket inhibitors, these new compounds appear to accelerate nucleotide exchange. This study highlights the efficiency of covalent docking as a tool for the discovery of chemically novel hits against challenging targets.

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