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Neutral ceramidase-active site inhibitor chemotypes and binding modes

Bioorganic Chemistry, ISSN: 0045-2068, Vol: 139, Page: 106747
2023
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Studies from State University of New York (SUNY) Stony Brook Further Understanding of Chemicals and Chemistry (Neutral Ceramidase-active Site Inhibitor Chemotypes and Binding Modes)

2023 OCT 04 (NewsRx) -- By a News Reporter-Staff News Editor at Chemicals & Chemistry Daily Daily -- Investigators publish new report on Chemicals and

Article Description

Ceramides impact a diverse array of biological functions and have been implicated in disease pathogenesis. The enzyme neutral ceramidase (nCDase) is a zinc-containing hydrolase and mediates the metabolism of ceramide to sphingosine (Sph), both in cells and in the intestinal lumen. nCDase inhibitors based on substrate mimetics, for example C6-urea ceramide, have limited potency, aqueous solubility, and micelle-free fraction. To identify non-ceramide mimetic nCDase inhibitors, hit compounds from an HTS campaign were evaluated in biochemical, cell based and in silico modeling approaches. A majority of small molecule nCDase inhibitors contained pharmacophores capable of zinc interaction but retained specificity for nCDase over zinc-containing acid and alkaline ceramidases, as well as matrix metalloprotease-3 and histone deacetylase-1. nCDase inhibitors were refined by SAR, were shown to be substrate competitive and were active in cellular assays. nCDase inhibitor compounds were modeled by in silico DOCK screening and by molecular simulation. Modeling data supports zinc interaction and a similar compound binding pose with ceramide. nCDase inhibitors were identified with notably improved activity and solubility in comparison with the reference lipid-mimetic C6-urea ceramide.

Bibliographic Details

Coant, Nicolas; Bickel, John D; Rahaim, Ronald; Otsuka, Yuka; Choi, Yong-Mi; Xu, Ruijuan; Simoes, Michael; Cariello, Chris; Mao, Cungui; Saied, Essa M; Arenz, Christoph; Spicer, Timothy P; Bannister, Thomas D; Tonge, Peter J; Airola, Michael V; Scampavia, Louis; Hannun, Yusuf A; Rizzo, Robert C; Haley, John D

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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