Sphinosine-1-phosphate receptors (S1P1-5R) are involved in regulating inflammation processes. Their agonists treat inflammatory illnesses, such as multiple sclerosis (MS), colitis, and other many autoimmune illness. S1P1 and S1P5 receptors are involved in the inflammation in the central nervous system, and thus are targets for treatment of MS. Recently, S1P5 structure was solved with the inverse agonist ONO-5340608 bound to the orthosteric site.1 We design drugs to target S1P5 specifically, using the V-Synthes 2.0 structure based screening.2 From a chemical space of more than 11 billion compounds, we narrowed down a list of 134 potential ligands to be tested experimentally. We saw that their binding poses were similar to the inverse agonist ONO-5430608, and differed to an extent from the S1P agonist. There were strong salt bridges and hydrogen bonds in the polar head groups of the ligands and the polar region of the orthosteric binding site, similar to that of both S1P and ONO-5430608. Unlike S1P, which had significant binding in a apolar region of the orthosteric binding site, the proposed ligands did not exhibit significant hydrophobic binding in the apolar region. Guided by the structural information, virtual screening for the new S1P5 ligands has revealed novel chemotypes with high ligand efficiency and S1P5 selectivity, as potential for therapeutics in the treatment of MS.

Drug design for S1P5 to treat Multiple sclerosis using V-synthes 2.0 method

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ACS Fall 2022

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