title: Identification of novel CERT ligands as potential ceramide trafficking inhibitors.
abstract: A highly compartmentalized enzymatic network regulates the pro-apoptotic and proliferative effects of sphingolipids. Over-conversion of ceramide (Cer) correlates with insensitivity to apoptosis signaling (in response to chemotherapy) and to drug resistance of cancer cells. De novo sphingomyelin biosynthesis relies on non-vesicular ceramide trafficking by the CERT (CERamide Transfer) protein. Therefore, blocking CERT transfer, thus leading to increased intracellular ceramide availability, represents a potential anticancer strategy. Our study is based on the implementation of an in vitro binding assay, supported by in silico molecular docking. It constitutes the first attempt to explore at the molecular level for the identification of novel CERT ligands. This approach is the first step toward in silico design and optimization of CERT inhibitor candidates, potentially relevant as innovative ceramide-transfer-targeting therapeutic agents.
authors.affiliation: SPCMIB, UMR-CNRS 5068-Université Paul Sabatier-Toulouse III, 118, route de Narbonne, F-31062 Toulouse Cedex 9 (France).
authors.forename: Cécile
authors.initials: C
authors.lastname: Santos
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rogriguez
authors.forename: Virginie
authors.initials: V
authors.lastname: Garcia
authors.forename: Daniela
authors.initials: D
authors.lastname: Moravčíková
authors.forename: Dušan
authors.initials: D
authors.lastname: Berkeš
authors.forename: Adam
authors.initials: A
authors.lastname: Daïch
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Cécile
authors.initials: C
authors.lastname: Baudoin-Dehoux
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ballereau
authors.forename: Yves
authors.initials: Y
authors.lastname: Génisson
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D002352:Carrier Proteins; D002518:Ceramides; D008024:Ligands
keywords: CERT; cancer; ceramide; docking; sphingolipids