Analysis of Edg-Like LPA Receptor-Ligand Interactions

Title:Analysis of Edg-Like LPA Receptor-Ligand Interactions

Volume: 21 Issue: 24

Author(s): Balazs Balogh, Tamas Pazmany and Peter Matyus

Affiliation:

Keywords: Docking, LPA antagonist, LPA agonist, lysophospholipid, lysophosphatidic acid.

Abstract: The phospholipid derivative lysophosphatidic acid (LPA) serves as a signalling molecule through the activation of LPA receptors, which belong to the G-protein-coupled receptors. From a pharmacological point of view, the (‘EDG-like’) LPA_1-3 receptors have attracted much attention, therefore we have also been focusing in our study on these subtypes. The LPA1receptors are widely expressed in the human body; interestingly, LPA₁ might have a role in the pathomechanism of obesity. In order to recognize key structural features of the molecular interactions of human LPA₁with its agonists, we built up the 3D structure of the LPA₁ through homology modeling. Next, LPA₁ agonists and antagonists were docked into the model. The mode of binding and the interactions between ligands and key amino acids (R3.28 and Q3.29) were consistent with mutagenesis assays and previously published models, indicating that this model is able to discriminate high-affinity compounds and may be useful for the development of novel agonists of LPA₁.

Homology models were also constructed for LPA₂ and LPA₃. All available agonists with published EC₅₀ values, antagonists with IC₅₀ values and compounds with K_i values for either of LPA₁, LPA₂ or LPA₃ were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA_1-3 receptors can discriminate high-affinity compounds identified in silico HTS studies and may be useful for the development of novel agonistsof LPA receptors. With a better understanding of the differences between LPA_1-3 receptors new, selective agonists and antagonist could be designed, which could be used in the therapy of various diseases with a better side-effect profile.

Cite this article as:

Balogh Balazs, Pazmany Tamas and Matyus Peter, Analysis of Edg-Like LPA Receptor-Ligand Interactions, Current Pharmaceutical Design 2015; 21 (24) . https://dx.doi.org/10.2174/1381612821666150216120500