7l0e
Crystal structure of bovine RPE65 in complex with gem-difluoro emixustat and palmitate
Structural highlights
FunctionRPE65_BOVIN Plays important roles in the production of 11-cis retinal and in visual pigment regeneration. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT. The enzymatic activity is linearly dependent of the expression levels and membrane association.[1] [2] [3] Publication Abstract from PubMedRecycling of all-trans-retinal to 11-cis-retinal through the visual cycle is a fundamental metabolic pathway in the eye. A potent retinoid isomerase (RPE65) inhibitor, (R)-emixustat, has been developed and tested in several clinical trials; however, it has not received regulatory approval for use in any specific retinopathy. Rapid clearance of this drug presents challenges to maintaining concentrations in eyes within a therapeutic window. To address this pharmacokinetic inadequacy, we rationally designed and synthesized a series of emixustat derivatives with strategically placed fluorine and deuterium atoms to slow down the key metabolic transformations known for emixustat. Crystal structures and quantum chemical analysis of RPE65 in complex with the most potent emixustat derivatives revealed the structural and electronic bases for how fluoro substituents can be favorably accommodated within the active site pocket of RPE65. We found a close ( approximately 3.0 A) F-pi interaction that is predicted to contribute approximately 2.4 kcal/mol to the overall binding energy. Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy.,Blum E, Zhang J, Zaluski J, Einstein DE, Korshin EE, Kubas A, Gruzman A, Tochtrop GP, Kiser PD, Palczewski K J Med Chem. 2021 Jun 24;64(12):8287-8302. doi: 10.1021/acs.jmedchem.1c00279. Epub, 2021 Jun 3. PMID:34081480[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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