In Silico Binding Analysis of a Zone 2 Modified Sphingosine Kinase Inhibitor
Session Title
Physical Sciences
Faculty Mentor
T. Christian Grattan, Ph.D.; grattanc@winthrop.edu
College
College of Arts and Sciences
Department
Chemistry, Physics & Geology
Faculty Mentor
T. Christian Grattan, Ph.D.
Abstract
Sphingosine-1-phosphate is a bioactive lipid mediator that has been shown to play a critical role in cell migration, survival, and proliferation. It is phosphorylated from sphingosine, which has the opposite effect on cells. Sphingosine inhibits cell proliferation and causes apoptosis. Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine into sphingosine-1-phosphate. Sphingosine kinase has two isoenzymes, sphingosine kinase 1 and 2. Sphingosine kinase 1 is ubiquitously expressed in most cancer cells where it has been linked to cell proliferation, migration, and survival. Based on this information, sphingosine kinase 1 has become a novel target for anticancer therapy. We analyzed the molecular properties of several zone 2 inhibitors of sphingosine kinase inhibitor 1 using an online molecular property analysis site called “molinspiration”. The inhibitors were then modeled using the Marvin’s Sketch computer software. The inhibitors were then uploaded into USCF Chimera with sphingosine kinase 1 and the docking analysis was conducted using Autodock Vina. The binding energies of each inhibitor were recorded from the docking analysis. These docking energies evaluated how well each inhibitor was able to bind to the docking site in silico. The optimal binding energy was achieved by replacing the pyrazole ring linker in a known sphingosine kinase 1 inhibitor, SKI-1, with a 2,5-substituted pyridine ring system. This information will be useful when determining the optimized inhibitors for Zone 2 in conjuction with other optimized sites to improve binding and efficacy of a modified sphingosine kinase inhibitor 1.
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Course Assignment
MCNR 300 - Fortner-Wood
Grant Support
Support was provided by an NIH-INBRE grant from the National Center for Research Resources and the National Institute for General Medical Sciences as well as the Winthrop University Department of Chemistry, Physics, and Geology. McNair Scholars Program
Start Date
16-4-2021 3:00 PM
In Silico Binding Analysis of a Zone 2 Modified Sphingosine Kinase Inhibitor
Sphingosine-1-phosphate is a bioactive lipid mediator that has been shown to play a critical role in cell migration, survival, and proliferation. It is phosphorylated from sphingosine, which has the opposite effect on cells. Sphingosine inhibits cell proliferation and causes apoptosis. Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine into sphingosine-1-phosphate. Sphingosine kinase has two isoenzymes, sphingosine kinase 1 and 2. Sphingosine kinase 1 is ubiquitously expressed in most cancer cells where it has been linked to cell proliferation, migration, and survival. Based on this information, sphingosine kinase 1 has become a novel target for anticancer therapy. We analyzed the molecular properties of several zone 2 inhibitors of sphingosine kinase inhibitor 1 using an online molecular property analysis site called “molinspiration”. The inhibitors were then modeled using the Marvin’s Sketch computer software. The inhibitors were then uploaded into USCF Chimera with sphingosine kinase 1 and the docking analysis was conducted using Autodock Vina. The binding energies of each inhibitor were recorded from the docking analysis. These docking energies evaluated how well each inhibitor was able to bind to the docking site in silico. The optimal binding energy was achieved by replacing the pyrazole ring linker in a known sphingosine kinase 1 inhibitor, SKI-1, with a 2,5-substituted pyridine ring system. This information will be useful when determining the optimized inhibitors for Zone 2 in conjuction with other optimized sites to improve binding and efficacy of a modified sphingosine kinase inhibitor 1.
