期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 58, 期 2, 页码 464-471出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.7b00399
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资金
- National Institutes of Health [R01 (5R01CA190408)]
- F30 Kirschstein-NRSA [1F30CA214015]
- Stand Up To Cancer American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]
- American Association for Cancer Research
- Israel Science Foundation [1097/16]
- Rising Tide Foundation
- Israel Cancer Research Foundation
- CIHR new investigator program
- Natural Sciences and Engineering Research Council of Canada [NSERC-2014-05218]
- National Institutes of Health Grant [5R01CA172667]
- scientific partner of SU2C
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-Ras(G12C). 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-Ras(G12C). 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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