Balazs Balogh, Tamas Pazmany and Peter Matyus Pages 3533 - 3547 ( 15 )
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<sub>1-3</sub> 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, LPA<sub>1</sub> might have a role in the pathomechanism of obesity. In order to recognize key structural features of the molecular interactions of human LPA<sub>1</sub>with its agonists, we built up the 3D structure of the LPA<sub>1</sub> through homology modeling. Next, LPA<sub>1</sub> 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 LPA<sub>1</sub>. </p> <p> Homology models were also constructed for LPA<sub>2</sub> and LPA<sub>3</sub>. All available agonists with published EC<sub>50</sub> values, antagonists with IC<sub>50</sub> values and compounds with K<sub>i</sub> values for either of LPA<sub>1</sub>, LPA<sub>2</sub> or LPA<sub>3</sub> were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA<sub>1-3</sub> 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<sub>1-3</sub> 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.
Docking, LPA antagonist, LPA agonist, lysophospholipid, lysophosphatidic acid.
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