ArticleJournal of medicinal chemistry2022
Reactivities of the Front Pocket N-Terminal Cap Cysteines in Human Kinases.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
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- Force Field Limitations of All-Atom Continuous Constant pH Molecular Dynamics.The journal of physical chemistry. B · 2024Article
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- Evidence of Gas Phase Glucosyl Transfer and Glycation in the CID/HCD-Spectra of S-Glucosylated Peptides.International journal of molecular sciences · 2024Article
- Machine Learning Models to Interrogate Proteome-Wide Covalent Ligandabilities Directed at Cysteines.JACS Au · 2024Article
- Targeting Cysteine Oxidation in Thrombotic Disorders.Antioxidants (Basel, Switzerland) · 2024Review
- Machine Learning Models to Interrogate Proteomewide Covalent Ligandabilities Directed at Cysteines.bioRxiv : the preprint server for biology · 2024Article
- Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.Drug design, development and therapy · 2024Article
- A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.RSC medicinal chemistry · 2023Article
- PTM-Psi: A python package to facilitate the computational investigation of post-translational modification on protein structures and their impacts on dynamics and functions.Protein science : a publication of the Protein Society · 2023Article
- Quantum Descriptors for Predicting and Understanding the Structure-Activity Relationships of Michael Acceptor Warheads.Journal of chemical information and modeling · 2023Article
- Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.ACS medicinal chemistry letters · 2023Article
- Analysis of the ERK Pathway Cysteinome for Targeted Covalent Inhibition of RAF and MEK Kinases.Journal of chemical information and modeling · 2023Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.