In silico Docking Studies of Fingolimod and S1P1 Agonists

Abstract

The sphingosine-1-phosphate receptor 1 (S1P 1), originally the endothelial differentiation gene 1 receptor (EDG-1), is one of five G protein-coupled receptors (GPCRs) S1P 1−5 that bind to and are activated by sphingosine-1-phosphate (S1P). The lipid S1P is an intermediate in sphingolipid homeostasis, and S1P 1 is a major medical target for immune system modulation; agonism of the receptor produces a myriad of biological responses, including endothelial cell barrier integrity, chemotaxis, lymphocyte trafficking/targeting, angiogenesis, as well as regulation of the cardiovascular system. Use of in silico docking simulations on the crystal structure of S1P 1 allows for pinpointing the residues within the receptor's active site that actively contribute to the binding of S1P, and point to how these specific interactions can be exploited to design more effective synthetic analogs to specifically target S1P 1 in the presence of the closely related receptors S1P 2 , S1P 3 , S1P 4 , and S1P 5. We examined the binding properties of the endogenous substrate as well as a selection of synthetic sphingosine-derived S1P 1 modulators of S1P 1 with in silico docking simulations using the software package Molecular Operating Environment R (MOE R). The modeling studies reveal the relevance of phosphorylation, i.e., the presence of a phosphate or phosphonate moiety within the substrate for successful binding to occur, and indicate which residues are responsible for S1P 1 binding of the most prominent sphingosine-1-phosphate receptor (S1PR) modulators, including fingolimod and its structural relatives. Furthermore, trends in steric preferences as for the binding of enantiomers to S1P 1 could be observed, facilitating future design of receptor-specific substrates to precisely target the active site of S1P 1 .

Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking

“…[ 40 ]. In contrast, the phosphate moiety of ML056 (W146) formed hydrogen bonds with Try29 and Arg120 and formed a metal contact with Arg120 (Additional file 1 : Fig.S1A); this binding mode has been reported by several studies [ 41 – 43 ]. Docking of components contained in BTWT to S1PR1 gave the lowest calculated binding energy conformation values, ranging from -13.00 to -5.84 kcal/mol; AA3 had the lowest value.…”

Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2

“…The only limitation is the cost of PET, especially for bigger sample studies. Modulators targeting S1PR1 are already FDA-approved therapeutics of treating multiple sclerosis ( 18 , 39 ), which could further accelerate its important role for treatment development in schizophrenia.…”

Differential sphingosine-1-phosphate receptor-1 protein expression in the dorsolateral prefrontal cortex between schizophrenia Type 1 and Type 2

“…Modulators targeting S1PR1 are already FDA-approved therapeutics of treating multiple sclerosis (Bross et al, 2020;Marciniak et al, 2020), which could further accelerate its important role for treatment development in schizophrenia.…”

“…The present study examines the differential expression of S1PR1 in the DLPFC of Type 1 and Type 2 schizophrenic patients at the protein level as a preliminary step towards the use of PET to distinguish Type 1 from Type 2 schizophrenia during life. S1PR1 radioligand has gained significant interest for in vivo targeted imaging of inflammation in brain diseases, with the recent FDA approval of the first orally administered S1PR1 receptor-targeted drug, FTY720 (Fingolimod) for multiple sclerosis (Marciniak et al, 2020). PET S1PR1 has recently gone into living humans successfully at Washington University in St. Louis (Liu et al, 2017;Liu et al, 2016;Liu et al, 2020;Luo et al, 2019).…”