2. Academic Validation
  3. Neutral ceramidase-active site inhibitor chemotypes and binding modes

Neutral ceramidase-active site inhibitor chemotypes and binding modes

  • Bioorg Chem. 2023 Oct:139:106747. doi: 10.1016/j.bioorg.2023.106747.
Nicolas Coant 1,  John D Bickel 2,  Ronald Rahaim 3,  Yuka Otsuka 3,  Yong-Mi Choi 4,  Ruijuan Xu 1,  Michael Simoes 5,  Chris Cariello 5,  Cungui Mao 1,  Essa M Saied 6,  Christoph Arenz 7,  Timothy P Spicer 3,  Thomas D Bannister 3,  Peter J Tonge 8,  Michael V Airola 4,  Louis Scampavia 3,  Yusuf A Hannun 9,  Robert C Rizzo 10,  John D Haley 11
Affiliations

Affiliations

  • 1 Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
  • 2 Department of Applied Mathematics, Stony Brook University, Stony Brook, NY 11794, USA.
  • 3 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA.
  • 4 Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA.
  • 5 Renaissance School of Medicine, Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
  • 6 Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.
  • 7 Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
  • 8 Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
  • 9 Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
  • 10 Department of Applied Mathematics, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
  • 11 Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Renaissance School of Medicine, Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
PMID: 37531819 DOI: 10.1016/j.bioorg.2023.106747
Abstract

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.

Keywords

Colorectal cancer; Neutral ceramidase; Neutral ceramidase inhibitor; nCDase.

Figures
Products