GPCR Structure and Function: Taking GPCR Drug Development and Discovery to the Next Level

Країна: США

Місто: Santa Fe

Тези до: 15.11.2017

Дати: 16.02.18 — 20.02.18

Е-мейл Оргкомітету:

Організатори: Keystone Symposia


G protein-coupled receptors (GPCRs) are a critical family of cell surface receptors that detect extracellular stimuli, facilitate intercellular communication and regulate cellular homeostasis. As such, GPCRs remain highly relevant drug discovery targets addressing key unmet medical needs. Recent advances in understanding GPCR signaling networks, coupled with the unraveling of structural details of GPCRs, their signaling partners, and in some cases their signaling complexes, have enhanced our understanding of GPCR function. These advances have provided researchers the basic tools to interrogate critical but diverse aspects of GPCR signaling, such as receptor conformation, receptor-effector specificity and the role of receptor subcellular distribution, in signaling efficacy. All of these factors may influence ligand binding and therefore have impact on drug discovery. The availability of atomic-resolution structures of GPCRs alongside the introduction of functional coupling (e.g., biased signaling) is providing the potential for physiologically tailored and therefore disease-specific therapies. However, challenges remain as the design of small molecule tools and potential drugs is both labor-intensive and very costly, requiring large chemical library screening campaigns. In addition, improvements are still needed in GPCR ligand selectivity, signaling specificity and appropriate kinetics to achieve maximal efficacy and reasonable safety. Rational ligand design could significantly reduce both time and cost of drug discovery. Viable approaches are currently being explored through the combination of molecular dynamic simulations, GPCR crystallization and biophysical analysis. Drug efficacy and safety improvements are slow to emerge and can be addressed by the development of physiologically relevant GPCR ligands. Targeting allosteric sites, hetero- and homo-dimers and specific signaling pathways could provide such context- and disease-specific regulation. This conference will highlight the latest developments in GPCR structure/function, ligand discovery and design, intracellular signaling pathways and their impact on modern drug discovery.

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