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How Reactive are Druggable Cysteines in Protein Kinases? by Ernest Awoonor-Williams; Christopher N. Rowley is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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Targeted covalent inhibitors (TCIs) have been successfully developed as high-affinity and selective inhibitors of enzymes of the protein kinase family. These drugs typically act by undergoing an electrophilic addition with an active-site cysteine residue, so design of a TCI begins with the identification of a "druggable" cysteine. These electrophilic additions generally require deprotonation of the thiol to form a reactive anionic thiolate, so the acidity of the residue is a critical factor. Few experimental measurements of the p K's of druggable cysteines have been reported, so computational prediction could prove to be very important in selecting reactive cysteine targets. Here we report the computed p K's of druggable cysteines in selected protein kinases that are of clinical relevance for targeted therapies. The p K's of the cysteines were calculated using advanced computational methods based on all-atom replica-exchange thermodynamic integration molecular dynamics simulations in explicit solvent. We found that the acidities of druggable cysteines within protein kinases are diverse and elevated, indicating enormous differences in their reactivity. Constant-pH molecular dynamics

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Author

Ernest Awoonor-Williams; Christopher N. Rowley

Published

2018

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Physical Sciences)