GPCRs constitute a major class of drug targets & modulating their signaling can
ID: 176017 • Letter: G
Question
GPCRs constitute a major class of drug targets & modulating their signaling can produce a wide range of pharmacological outcomes. With the growing number of high-resolution GPCR crystal structures, we have the unprecedented opportunity to leverage structure-based drug design techniques
A) Describe the structure & functionality of GPCRs and identify the commonly druggable sites on the protein
B) Describe the types of ligands that commonly bind GPCRs
C) Describe techniques that are used to study drug interactions with GPCRs
Explanation / Answer
A) These GPCRs have seven transmembrane domains. They associate with heterotrimeric G-proteins and are composed of three sub units : alpha,beta and gamma. The subunits are attached to the membrane surface by covalently attached lipid molecules. When a ligand binds, the receptor activates the attached G-protein by causing the exchange of GTP (yellow) for GDP (red). The activated G-protein then dissociates into an alpha (G-alpha) and a beta-gamma complex. G-alpha bound to GTP is active, and can diffuse along the membrane surface to activate (and sometimes inhibit) target proteins, often enzymes that generate second messengers.
The common druggable sites on the protein are class A,B,C,D and E sites.
B) The types of ligands that bind to GPCRs are proteins,hydrophobic steroid molecules,gases like nitric oxide and water soluble polar ligands.
C) Techniques used to study drug interactions with GPCRs:
- Molecular modeling strategy to predict the interaction of studied molecule with a set of target candidates.
- bioinformatic strategy.
- chemoinformatic strategy.
- molecular docking.
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