Computational Approach to Ligand Discovery for LPA GPCR and PPAR

University Of Memphis, Memphis TN

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Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are phospholipid growth factors involved in signaling pathways that regulate vascular remodeling, immune cell trafficking and development of neuronal and cardiovascular systems. LPA can initiate the early steps of neointima formation, demonstrating the importance of additional studies on its role in cardiovascular disease. The proposed studies outline varied approaches that address a single fundamental question. Namely, what structural characteristics confer selective agonist and/or antagonist activity at individual phospholipid growth factor receptors? This question is important because this receptor family is involved in diverse biological responses related to cardiovascular disease and carcinogenesis that remain incompletely characterized due to overlapping expression patterns and a lack of receptor-selective pharmacological probes. Our prior structural characterization of both agonist and antagonist binding to these receptors uniquely positions us to answer this fundamental question and provide much-needed research tools. The question will be addressed through the following specific aims: 1. Validate the LPA GPCR antagonist binding site using a model-driven mutagenesis strategy. 2. Determine the NMR structure of the computationally-designed extracellular loop mimetic peptides and evaluate their applicability to screen for antagonist interactions. 3. Develop predictive computational models (QSAR and pharmacophore) of agonist/antagonist action at LPA GPCR and PPARgamma receptors and apply them in the discovery of novel agonist and antagonist lead compound architectures. This research has the potential to reveal new leads for the development of therapeutic compounds for the prevention and treatment of cardiovascular disease. Cardiovascular disease accounted for 1 in every 2.6 deaths in the United States in 2001 and the World Health Organization indicates that 16.7 million annual deaths occur globally due to cardiovascular disease. Additional therapeutic strategies for this disease are critically needed and of broad benefit to public health. The LPA receptors additional stimulate cancer cell motility. Agents that block activation of these receptors may therefore inhibit the invasiveness and metastasis of tumors, serving as important chemotherapeutic leads. This research can therefore lead to new treatments for cardiovascular disease and cancer.