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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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The Two-State Receptor Model01:29

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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
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G-protein Coupled Receptors01:21

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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GPCR Desensitization01:12

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Structure-Based Consensus Scoring Scheme for Selecting Class A Aminergic GPCR Fragments.

Ádám A Kelemen, Róbert Kiss, György G Ferenczy

  • 1Infarmatik, Inc. , 113 Barksdale Professional Center, Newark, Delaware 19711, United States.

Journal of Chemical Information and Modeling
|January 14, 2016
PubMed
Summary
This summary is machine-generated.

A new virtual screening method (FrACS) effectively designs targeted fragment libraries for aminergic G-protein coupled receptors (GPCRs), crucial for central nervous system drug discovery.

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Aminergic G-protein coupled receptors (GPCRs) are key targets for central nervous system (CNS) diseases.
  • Existing drug discovery methods for GPCRs require optimization.

Purpose of the Study:

  • To develop a structure-based consensus virtual screening scheme for designing targeted fragment libraries against class A aminergic GPCRs.
  • To improve the efficiency and accuracy of GPCR-targeted drug discovery.

Main Methods:

  • Clustering of X-ray structures to select representative aminergic GPCRs.
  • Development of a consensus scoring protocol (FrACS) using known ligands and decoys.
  • Retrospective and prospective validation of the FrACS method on public and in-house datasets.

Main Results:

  • The FrACS method demonstrated improved enrichment compared to stand-alone structures.
  • Retrospective validation showed 8-17-fold enrichments for aminergic targets.
  • Prospective validation identified six active fragments against 5-HT6 serotonin receptors with low micromolar or submicromolar IC50 values.

Conclusions:

  • The developed methodology is effective for designing focused class A GPCR fragment libraries.
  • FrACS enables efficient screening of large compound collections and virtual databases.
  • This approach aids in the discovery of novel CNS-targeting therapeutics.