S1PR1 modulators in multiple sclerosis: Efficacy, safety, comparison, and chemical structure insights

Kandjani, Omid Jamshidi; Yaqoubi, Shadi; Vahdati, Samad Shams; Borhannejad, Behnam; Dastmalchi, Siavoush; Alizadeh, Ali Akbar

doi:10.1016/j.ejmech.2023.115182

Cited by 5 publications

(2 citation statements)

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“…As a result, lymphocytes are confined within lymphoid tissues 8,9 . This mechanism makes S1PR1 a valuable target for treating autoimmune diseases such as Multiple Sclerosis (MS) [10][11][12] , tackling transplant rejections, and addressing conditions like Pulmonary Fibrosis 11,13,14 . The receptor subtypes S1PR1, S1PR2 and S1PR3 are primarily expressed in the cardiovascular, central nervous, and immune systems, whereas the expression of S1PR4 and S1PR5 is re-stricted to the immune and nervous systems 15,16 .…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Hence, this limits the clinical use of Fingolimod. In contrast, second-generation S1P receptor modulators such as Siponimod, Ozanimod, and Ponesimod are more selective for S1PR1 and S1PR5 over S1PR2, S1PR3, and S1PR4, resulting in fewer side effects 9,11,12 . Understanding the mechanisms of action of these next-generation drugs is crucial for developing strategies to enhance drug selectivity in GPCR therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Selective Activation of GPCRs: Molecular Dynamics Shows Siponimod Binds but Fails to Activate S1PR2 Unlike S1PR1

Soniya,

Nanduru,

Halder

2024

Preprint

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Understanding drug selectivity is crucial for designing effective medications that target specific proteins while minimizing off-target interactions, thus optimizing therapeutic outcomes. Although biochemical and cellular assays provide valuable insights on functional characterization, they offer limited understanding on molecular details of selectivity, particularly for targets within large families of structurally and functionally similar proteins. In such situations, carefully designed computational studies can complement experimental approaches, bridging gaps and deepening our understanding of drug selectivity mechanisms. In this study, Molecular Dynamics (MD) simulations along with structural bioinformatics methods have been used to examine the selectivity of Siponimod, an FDA-approved drug, towards sphingosine-1-phosphate receptor 1 (S1PR1) to treat Multiple Sclerosis (MS). Specifically, we investigated why Siponimod activates S1PR1 but not S1PR2, even though both receptors belong to the same sub-family of G Protein-Coupled Receptors (GPCRs). Contrary to the previous hypothesis based on molecular docking, MD simulations showed that Siponimod can bind to S1PR2 with anin silico-determined affinity comparable to that of S1PR1. Comparing the dynamics of Siponimod-bound S1PR2 with S1P-bound S1PR2 revealed that the transmission switches necessary for downstream biological activity are activated by S1P but not by Siponimod. Whereas, both S1P and Siponimod activate those transmission switches in S1PR1. A few crucial residues in S1PR2 were also identified that can be leveraged to optimize molecules to bind selectively to S1PR1 over S1PR2. Through our study, we showed thatin silicoapproaches can help in understanding the ligand induced structural changes and aid in developing and optimizing drugs for GPCRs, the most abundant class of membrane proteins in the human genome and the largest family of membrane receptors targeted by approved drugs.

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