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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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Structure-Activity Relationships and Drug Design01:28

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Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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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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Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

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Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
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Separation of...
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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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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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Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
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A desirability function-based scoring scheme for selecting fragment-like class A aminergic GPCR ligands.

Ádám A Kelemen1, György G Ferenczy, György M Keserű

  • 1Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok Körútja 2, Budapest, 1117, Hungary.

Journal of Computer-Aided Molecular Design
|October 20, 2014
PubMed
Summary

A new scoring system, Fragment-based drug discovery desirability score (FrAGS), aids in designing fragment libraries targeting aminergic G protein-coupled receptors (GPCRs). This method optimizes fragment selection for drug discovery efforts.

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Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Pharmacology

Background:

  • Fragment-based drug discovery (FBDD) is a key strategy for identifying novel drug leads.
  • Aminergic G protein-coupled receptors (GPCRs) are crucial drug targets, but developing targeted fragment libraries remains challenging.
  • Existing methods for fragment selection may not adequately capture properties relevant to GPCR binding.

Purpose of the Study:

  • To develop and validate a physicochemical property-based desirability scoring scheme for designing fragment libraries targeting class A aminergic GPCRs.
  • To create a quantitative score (FrAGS) that integrates key molecular properties predictive of fragment activity against aminergic GPCRs.
  • To assess the utility of the FrAGS score in optimizing fragment selection for drug discovery.

Main Methods:

  • Analysis of physicochemical property distributions (log D, PSA, pKa, N atoms, O atoms, rotatable bonds) of known aminergic GPCR-active fragments from the ChEMBL database.
  • Development of a desirability function-based scoring algorithm (FrAGS) integrating these properties.
  • Validation of the FrAGS scoring scheme using public and proprietary experimental screening data.

Main Results:

  • A novel scoring scheme, FrAGS, was successfully developed, integrating multiple physicochemical properties.
  • The FrAGS score effectively reflects the property distributions of known active fragments against aminergic GPCRs.
  • Validation confirmed the scoring scheme's suitability for designing targeted fragment libraries and preprocessing fragments for screening.

Conclusions:

  • The FrAGS scoring scheme provides a valuable tool for the rational design of fragment libraries specifically for class A aminergic GPCR targets.
  • This approach can enhance the efficiency of fragment-based drug discovery by prioritizing fragments with desirable physicochemical properties.
  • The FrAGS score may serve as a useful preprocessing step for both structure-based virtual screening and experimental screening.