title: Analysis of Edg-Like LPA Receptor-Ligand Interactions.
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') LPA1-3 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 Ki values for either of LPA1, LPA2 or LPA3 were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA1-3 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 LPA1-3 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.
authors: Balazs
authors: B
authors: Balogh
authors: Tamas
authors: T
authors: Pazmany
authors: Bionics Innovation Center, 1083 Budapest, Prater u. 50/A., Hungary. matyus.peter@pharma.semmelweis-univ.hu.
authors: Peter
authors: P
authors: Matyus
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008246:Lysophospholipids / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: D008024:Ligands; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid