In Silico Identification of Novel Orthosteric Inhibitors of Sphingosine Kinase 1 (SK1).
BACKGROUND
Sphingosine kinase 1 (SK1) overexpression and elevated sphingosine-1-phosphate (S1P) levels have been correlated with many disease states from cancer to inflammatory diseases to diabetes. Even though SK1 inhibitors are of consideberable interest as effective chemotherapeutic agents, poor potency, lack of selectivity and poor pharmacokinetic properties have been major problems in the first generation SK1 inhibitors.


OBJECTIVE
There is an urgent need for the discovery of novel in vivo, stable selective SK1 inhibitors with improved potency. The primary object of this study was to identify potential novel leads for orthosteric inhibition of SK1.


METHODS
We propose a series of compounds from different chemotypes as potential selective SK1 inhibitors via virtual screening of the ZINC database using ligand-based and structure-based pharmacophore models, molecular docking, substructure search, selectivity calculations. Molecular dynamics (MD) simulations revealed key insights into the binding mode and the stability of the SK1-ligand complex.


RESULTS
Ten ligands were proposed as potential SK1 inhibitors based on the high induced fit docking scores, BEI, LLE and %HOA. Ligands 2, 3, 5 and 9 were found to be selective toward SK1 with favorable binding free energy of - 95 ± 5 kcal/mol. MD simulation of ligand 5 showed that the ligand-SK1 complex reached equilibrium with favorable hydrogen bonding and hydrophobic interactions. The four selective compounds have less than 0.24 similarity with previously discovered potent inhibitors.


CONCLUSIONS
The proposed compounds may serve as potential novel leads for orthosteric inhibition of SK1.
Department of Computational Science and Engineering, Bogazici University, Istanbul, Turkey.
Ozge
O
Bayraktar
Department of Computational Science and Engineering, Bogazici University, Istanbul, Turkey.|Department of Chemical Engineering, Bogazici University, Istanbul, Turkey.
Elif
E
Ozkirimli
Department of Computational Science and Engineering, Bogazici University, Istanbul, Turkey.|Department of Chemical Engineering, Bogazici University, Istanbul, Turkey.
Kutlu O
KO
Ulgen
D001665:Binding Sites; D003198:Computer Simulation; D062313:Databases, Pharmaceutical; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D000099157:Sphingosine Kinase
D008024:Ligands; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D000099157:Sphingosine Kinase
3D-QSAR; Sphingosine kinase 1; cancer; docking; inhibitor; molecular dynamics; pharmacophore modeling; sphingosine-1-phosphate