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

A. Pavlic, H. Poelman, G. Wasilewski, K. Wichapong, P. Lux, C. Maassen, E. Lutgens, L.J. Schurgers, C.P. Reutelingsperger, G.A.F. Nicolaes*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 mu M. Further analysis showed that five compounds presented with IC(50)s lower than 2 mu M. 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.
Original languageEnglish
Article number2027
Number of pages21
JournalInternational Journal of Molecular Sciences
Volume24
Issue number3
DOIs
Publication statusPublished - 1 Feb 2023

Keywords

  • drug discovery
  • virtual ligand screening
  • vascular calcification
  • SMPD3
  • nSMase2
  • small molecules
  • extracellular vesicles
  • C2 DOMAIN
  • DISCOVERY
  • DESIGN
  • PREDICTION
  • PRECISION
  • MECHANISM
  • DOCKING
  • CALCIUM
  • DISEASE
  • SURFLEX

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