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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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...
Drug-Receptor Bonds01:25

Drug-Receptor Bonds

Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
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Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
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The Two-State Receptor Model01:29

The Two-State Receptor Model

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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Drug Binding to Blood Components01:30

Drug Binding to Blood Components

When drugs enter systemic circulation, they interact with various components of the blood, including proteins such as human serum albumin (HSA), α1-acid glycoprotein (AAG), lipoproteins, globulins, and red blood cells (RBCs).
HSA is the most abundant plasma protein and is vital in drug binding. It contains distinct drug-binding sites, with different drugs exhibiting affinity for specific sites. There are three main drug-binding domains for HSA: sites I, II, and III. These domains are further...

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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

Published on: September 13, 2013

Drugging all RAS isoforms with one pocket.

Dirk Kessler1, Andreas Bergner1, Jark Böttcher1

  • 1Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co. KG, 1121 Vienna, Austria.

Future Medicinal Chemistry
|August 12, 2020
PubMed
Summary
This summary is machine-generated.

New research explores targeting the switch I/II pocket to develop drugs for all RAS isoforms, including KRAS, NRAS, and HRAS, addressing undrugged cancers. This approach aims to overcome limitations of current KRAS G12C inhibitors.

Keywords:
BI-2852GTPaseKRASsmall molecule inhibitors

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Activating mutations in RAS genes (KRAS, NRAS, HRAS) are key drivers in many human cancers.
  • Current KRAS G12C inhibitors target the 'off state' but leave many cancers undrugged.
  • NRAS, HRAS, and 'on state' KRAS remain undrugged targets.

Purpose of the Study:

  • To elucidate inhibitor binding modes in KRAS, NRAS, and HRAS.
  • To explore the potential of the switch I/II pocket for targeting all RAS isoforms.
  • To discuss future strategies for developing pan-RAS inhibitors.

Main Methods:

  • Structural analysis of inhibitor binding.
  • Biochemical assays to characterize inhibitor interactions.
  • Computational modeling to understand binding dynamics.

Main Results:

  • Detailed elucidation of inhibitor binding modes in KRAS, NRAS, and HRAS.
  • Identification of the switch I/II pocket as a potential target for broad RAS inhibition.
  • Demonstration of nanomolar inhibitor BI-2852 binding to the switch I/II pocket.

Conclusions:

  • The switch I/II pocket offers a promising target for developing drugs against all RAS isoforms.
  • Targeting this pocket could overcome limitations of current KRAS G12C-specific therapies.
  • Future strategies should focus on leveraging this pocket for pan-RAS drug development.