Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation.

Gebhard ThomaEric VangrevelingheAlexandre LuneauPhilippe PiechonChristian BeerliHans-Guenter Zerwes

Published in: ACS medicinal chemistry letters (2023)

We present a novel concept for the design of supersoft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3 . Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases. We demonstrate that the hydrolysis in human blood and the subsequent shape change lead to the deactivation of 2 .

Keyphrases

molecular dynamics simulations
endothelial cells
high glucose
drug induced
crystal structure
wound healing
induced pluripotent stem cells
molecular dynamics
hydrogen peroxide
single molecule
protein kinase
pluripotent stem cells
nitric oxide
dna binding
loop mediated isothermal amplification
quantum dots