基于萘的鞘氨醇激酶2抑制剂的构效关系研究与分子模拟
Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors.
作者信息
Congdon Molly D, Kharel Yugesh, Brown Anne M, Lewis Stephanie N, Bevan David R, Lynch Kevin R, Santos Webster L
机构信息
Department of Chemistry, Department of Biochemistry, and Virginia Tech Center for Drug Discovery, Virginia Tech , Blacksburg, Virginia 24061, United States.
Department of Pharmacology, University of Virginia , Charlottesville, Virginia 22908, United States.
出版信息
ACS Med Chem Lett. 2016 Feb 2;7(3):229-34. doi: 10.1021/acsmedchemlett.5b00304. eCollection 2016 Mar 10.
Abstract
The two isoforms of sphingosine kinase (SphK1 and SphK2) are the only enzymes that phosphorylate sphingosine to sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in a broad range of cellular processes including migration, proliferation, and inflammation. SphKs are targets for various diseases such as cancer, fibrosis, and Alzheimer's and sickle cell disease. Herein, we disclose the structure-activity profile of naphthalene-containing SphK inhibitors and molecular modeling studies that reveal a key molecular switch that controls SphK selectivity.
摘要
鞘氨醇激酶的两种同工型（SphK1和SphK2）是仅有的将鞘氨醇磷酸化为1-磷酸鞘氨醇（S1P）的酶，1-磷酸鞘氨醇是一种多效性脂质介质，参与包括迁移、增殖和炎症在内的广泛细胞过程。鞘氨醇激酶是癌症、纤维化、阿尔茨海默病和镰状细胞病等多种疾病的治疗靶点。在此，我们揭示了含萘鞘氨醇激酶抑制剂的构效关系以及分子模拟研究，这些研究揭示了一个控制鞘氨醇激酶选择性的关键分子开关。
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