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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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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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Natural selection is an evolutionary process in which individuals with survival-promoting traits reproduce at higher rates. These favorable traits become more common within a population or species. Naturally selected traits initially arise via random genetic mutations. In order for selection to occur, there must be variation within a population, the trait controlling the variation must be heritable, and there must be an evolutionary advantage for variation in the trait.
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Natural selection influences the frequencies of particular alleles and phenotypes within populations in several different ways. Primarily, natural selection can be directional, stabilizing, or disruptive. Directional selection favors one extreme trait and shifts the population towards that phenotype while selecting against individuals displaying alternate traits. Stabilizing selection favors an intermediate trait with a narrow range of variation. Deviation from the optimal phenotype towards an...
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Organisms that are well-adapted to their environment are more likely to survive and reproduce. However, natural selection does not lead to perfectly adapted organisms. Several factors constrain natural selection.
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Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets.

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Large library docking struggles to identify selective drug candidates. While effective against intended targets, it frequently fails to ensure selectivity against off-targets, necessitating new computational strategies.

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Area of Science:

  • Medicinal Chemistry
  • Computational Drug Discovery
  • Pharmacology

Background:

  • Large library docking is a key computational method for identifying potential drug candidates.
  • Achieving both on-target activity and off-target selectivity is crucial for drug safety and efficacy.
  • Current docking strategies may not adequately predict selectivity against undesired targets.

Purpose of the Study:

  • To evaluate the efficacy of large library docking in identifying molecules with dual on-target activity and antitarget selectivity.
  • To assess the performance of docking against both intended (on-targets) and undesired (antitargets) receptors.
  • To investigate the challenges in achieving receptor selectivity using computational screening.

Main Methods:

  • Utilized large library docking to screen for ligands against dopamine D2 and serotonin 5-HT2A receptors, seeking selectivity against histamine H1.
  • Conducted a second campaign to find kappa-opioid receptor ligands selective against the mu-opioid receptor.
  • Analyzed hit rates and binding affinities for both on-targets and antitargets.

Main Results:

  • Hit rates for on-targets (40-63%) were comparable to those for antitargets, despite screening for selectivity.
  • Identified ligands often showed similar or higher affinities for antitargets compared to on-targets.
  • Achieving selectivity was challenging; only occasional molecules, like a mid-nanomolar D2/5-HT2A ligand with 21-fold H1 selectivity, demonstrated the desired profile.

Conclusions:

  • Large library docking faces significant challenges in reliably predicting and achieving antitarget selectivity.
  • False negatives against antitargets are a critical issue in docking screens, potentially leading to undesired side effects.
  • Novel computational strategies are required to improve the prediction of selectivity and reduce off-target binding in drug discovery.