PMID- 37531819 OWN - NLM STAT- MEDLINE DCOM- 20230815 LR - 20240425 IS - 1090-2120 (Electronic) IS - 0045-2068 (Print) IS - 0045-2068 (Linking) VI - 139 DP - 2023 Oct TI - Neutral ceramidase-active site inhibitor chemotypes and binding modes. PG - 106747 LID - S0045-2068(23)00408-X [pii] LID - 10.1016/j.bioorg.2023.106747 [doi] AB - 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. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Coant, Nicolas AU - Coant N AD - Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Bickel, John D AU - Bickel JD AD - Department of Applied Mathematics, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Rahaim, Ronald AU - Rahaim R AD - The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. FAU - Otsuka, Yuka AU - Otsuka Y AD - The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. FAU - Choi, Yong-Mi AU - Choi YM AD - Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Xu, Ruijuan AU - Xu R AD - Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Simoes, Michael AU - Simoes M AD - Renaissance School of Medicine, Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Cariello, Chris AU - Cariello C AD - Renaissance School of Medicine, Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Mao, Cungui AU - Mao C AD - Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Saied, Essa M AU - Saied EM AD - Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt. FAU - Arenz, Christoph AU - Arenz C AD - Institute for Chemistry, Humboldt Universitat zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany. FAU - Spicer, Timothy P AU - Spicer TP AD - The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. FAU - Bannister, Thomas D AU - Bannister TD AD - The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. FAU - Tonge, Peter J AU - Tonge PJ AD - Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Airola, Michael V AU - Airola MV AD - Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA. FAU - Scampavia, Louis AU - Scampavia L AD - The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA. FAU - Hannun, Yusuf A AU - Hannun YA AD - Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: yusuf.hannun@stonybrookmedicine.edu. FAU - Rizzo, Robert C AU - Rizzo RC AD - Department of Applied Mathematics, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: robert.rizzo@stonybrook.edu. FAU - Haley, John D AU - Haley JD AD - 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: john.haley@stonybrookmedicine.edu. LA - eng GR - S10 OD030330/OD/NIH HHS/United States GR - R01 CA221948/CA/NCI NIH HHS/United States GR - S10 OD025279/OD/NIH HHS/United States GR - R01 CA218678/CA/NCI NIH HHS/United States GR - S10 OD026857/OD/NIH HHS/United States GR - R35 GM126906/GM/NIGMS NIH HHS/United States GR - T32 GM136572/GM/NIGMS NIH HHS/United States GR - P01 CA097132/CA/NCI NIH HHS/United States GR - R35 GM128666/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230727 PL - United States TA - Bioorg Chem JT - Bioorganic chemistry JID - 1303703 RN - 0 (Ceramides) RN - 038753E78J (N-caproylsphingosine) RN - EC 3.5.1.23 (Neutral Ceramidase) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Catalytic Domain MH - *Ceramides/chemistry MH - *Neutral Ceramidase/antagonists & inhibitors MH - Sphingosine/chemistry PMC - PMC10681040 MID - NIHMS1944191 OTO - NOTNLM OT - Colorectal cancer OT - Neutral ceramidase OT - Neutral ceramidase inhibitor OT - nCDase COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/08/03 01:06 MHDA- 2023/08/14 06:42 PMCR- 2023/11/27 CRDT- 2023/08/02 18:06 PHST- 2023/06/21 00:00 [received] PHST- 2023/07/18 00:00 [revised] PHST- 2023/07/20 00:00 [accepted] PHST- 2023/08/14 06:42 [medline] PHST- 2023/08/03 01:06 [pubmed] PHST- 2023/08/02 18:06 [entrez] PHST- 2023/11/27 00:00 [pmc-release] AID - S0045-2068(23)00408-X [pii] AID - 10.1016/j.bioorg.2023.106747 [doi] PST - ppublish SO - Bioorg Chem. 2023 Oct;139:106747. doi: 10.1016/j.bioorg.2023.106747. Epub 2023 Jul 27.