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dc.contributor.authorLiu, Ruibin
dc.contributor.authorZhan, Shaoqi
dc.contributor.authorChe, Ye
dc.contributor.authorShen, Jana
dc.date.accessioned2022-02-04T14:24:09Z
dc.date.available2022-02-04T14:24:09Z
dc.date.issued2021-10-14
dc.identifier.urihttp://hdl.handle.net/10713/17878
dc.description.abstractThe front pocket (FP) N-terminal cap (Ncap) cysteine is the most popular site of covalent modification in kinases. A long-standing hypothesis associates the Ncap position with cysteine hyper-reactivity; however, traditional computational predictions suggest that the FP Ncap cysteines are predominantly unreactive. Here we applied the state-of-the-art continuous constant pH molecular dynamics (CpHMD) to test the Ncap hypothesis. Simulations found that the Ncap cysteines of BTK/BMX/TEC/ITK/TXK, JAK3, and MKK7 are reactive to varying degrees; however, those of BLK and EGFR/ERBB2/ERBB4 possessing a Ncap+3 aspartate are unreactive. Analysis suggested that hydrogen bonding and electrostatic interactions drive the reactivity, and their absence renders the Ncap cysteine unreactive. To further test the Ncap hypothesis, we examined the FP Ncap+2 cysteines in JNK1/JNK2/JNK3 and CASK. Our work offers a systematic understanding of the cysteine structure-reactivity relationship and illustrates the use of CpHMD to differentiate cysteines toward the design of targeted covalent inhibitors with reduced chemical reactivities.en_US
dc.description.urihttps://doi.org/10.1021/acs.jmedchem.1c01186en_US
dc.description.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/pmc8812259/en_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofJournal of Medicinal Chemistryen_US
dc.titleReactivities of the Front Pocket N-Terminal Cap Cysteines in Human Kinases.en_US
dc.typeArticleen_US
dc.identifier.doi10.1021/acs.jmedchem.1c01186
dc.identifier.pmid34647463
dc.source.journaltitleJournal of medicinal chemistry
dc.source.volume65
dc.source.issue2
dc.source.beginpage1525
dc.source.endpage1535
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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