title: Identification of small molecule sphingomyelin synthase inhibitors.
abstract: Sphingomyelin synthase (SMS), which catalyzes ceramide as one of the substrates to produce sphingomyelin, is a critical factor in the sphingolipid biosynthesis pathway. Recent studies indicated that SMS could serve as a novel potential drug target for the treatment of various metabolic diseases such as insulin resistance and atherosclerosis. However, very few small-molecule inhibitors of SMS are known. In this study, we performed structure-based virtual screening in combination with chemical synthesis and bioassay and discovered a class of small-molecule SMS inhibitors. The most potent compound exhibited an IC50 value lower than 20 μM in an in vitro enzymatic assay. To the best of our knowledge, this is the first time that small-molecule SMS inhibitors with potency close to the micromolar range are publicly revealed. The structure-activity relationship demonstrated by this class of compounds provides insights into the structural features that are essential for effective SMS inhibition.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Deng
authors.affiliation: State Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, People's Republic of China.
authors.forename: Fu
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lou
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Ding
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China.
authors.forename: Xiancheng
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, People's Republic of China. Electronic address: wangrx@mail.sioc.ac.cn.
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai 201203, People's Republic of China. Electronic address: dyye@shmu.edu.cn.
authors.forename: Deyong
authors.initials: D
authors.lastname: Ye
mesh_terms: D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D054852:Small Molecule Libraries; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups)
keywords: Atherosclerosis; Small-molecule inhibitors; Sphingomyelin synthase; Structure-based virtual screening