Inhibition of Neutral Sphingomyelinase 2 by Novel Small Molecule Inhibitors Results in Decreased Release of Extracellular Vesicles by Vascular Smooth Muscle Cells and Attenuated Calcification

Autor:	Angelina Pavlic, Hessel Poelman, Grzegorz Wasilewski, Kanin Wichapong, Petra Lux, Cecile Maassen, Esther Lutgens, Leon J. Schurgers, Chris P. Reutelingsperger, Gerry A. F. Nicolaes
Přispěvatelé:	RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, Biochemie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - Vessels
Jazyk:	angličtina
Rok vydání:	2023
Předmět:	MECHANISM PREDICTION Organic Chemistry SURFLEX C2 DOMAIN General Medicine Catalysis CALCIUM DISEASE Computer Science Applications drug discovery Inorganic Chemistry small molecules PRECISION nSMase2 DESIGN virtual ligand screening vascular calcification DISCOVERY DOCKING Physical and Theoretical Chemistry extracellular vesicles Molecular Biology Spectroscopy SMPD3
Zdroj:	International Journal of Molecular Sciences, 24(3):2027. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences Volume 24 Issue 3 Pages: 2027
ISSN:	1422-0067 1661-6596
Popis:	Vascular calcification (VC) is an important contributor and prognostic factor in the pathogenesis of cardiovascular diseases. VC is an active process mediated by the release of extracellular vesicles by vascular smooth muscle cells (VSMCs), and the enzyme neutral sphingomyelinase 2 (nSMase2 or SMPD3) plays a key role. Upon activation, the enzyme catalyzes the hydrolysis of sphingomyelin, thereby generating ceramide and phosphocholine. This conversion mediates the release of exosomes, a type of extracellular vesicles (EVs), which ultimately forms the nidus for VC. nSMase2 therefore represents a drug target, the inhibition of which is thought to prevent or halt VC progression. In search of novel druglike small molecule inhibitors of nSMase2, we have used virtual ligand screening to identify potential ligands. From an in-silico collection of 48,6844 small druglike molecules, we selected 996 compounds after application of an in-house multi-step procedure combining different filtering and docking procedures. Selected compounds were functionally tested in vitro; from this, we identified 52 individual hit molecules that inhibited nSMase2 activity by more than 20% at a concentration of 150 µM. Further analysis showed that five compounds presented with IC50s lower than 2 µM. Of these, compounds ID 5728450 and ID 4011505 decreased human primary VSMC EV release and calcification in vitro. The hit molecules identified here represent new classes of nSMase2 inhibitors that may be developed into lead molecules for the therapeutic or prophylactic treatment of VC.
Databáze:	OpenAIRE
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