Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors

Molly D Congdon; Yugesh Kharel; Anne M Brown; Stephanie N Lewis; David R Bevan; Kevin R Lynch; Webster L Santos

doi:10.1021/acsmedchemlett.5b00304

Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors

ACS Med Chem Lett. 2016 Feb 2;7(3):229-34. doi: 10.1021/acsmedchemlett.5b00304. eCollection 2016 Mar 10.

Authors

Molly D Congdon¹, Yugesh Kharel², Anne M Brown¹, Stephanie N Lewis¹, David R Bevan¹, Kevin R Lynch², Webster L Santos³

Affiliations

¹ Department of Chemistry, Department of Biochemistry, and Virginia Tech Center for Drug Discovery, Virginia Tech , Blacksburg, Virginia 24061, United States.
² Department of Pharmacology, University of Virginia , Charlottesville, Virginia 22908, United States.
³ Department of Chemistry, Department of Biochemistry, and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States; Department of Chemistry, Department of Biochemistry, and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.

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.

Keywords: Sphingosine; molecular docking; sphingosine kinase; sphingosine-1-phosphate; structure−activity relationship.

Abstract

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