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Related Concept Videos

Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Directly Acting Muscle Relaxants: Dantrolene and Botulinum Toxin01:26

Directly Acting Muscle Relaxants: Dantrolene and Botulinum Toxin

Directly acting muscle relaxants like dantrolene and botulinum toxin (BoNT) have distinct mechanisms and applications. Dantrolene, a hydantoin derivative, acts on the ryanodine receptor (RYR1) in skeletal muscle cells. RYR1 are calcium channels present at the sarcoplasmic reticulum membrane. In response to excitation, they release calcium ions from the sarcoplasmic reticulum to the cytosol. Calcium promotes actin-myosin-mediated contraction of muscles.
The binding of dantrolene to the RYR1...
Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers01:25

Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers

β-adrenergic antagonists, or β-blockers, modulate the sympathetic nervous system by targeting β-adrenoceptors and inhibiting catecholamine-mediated sympathetic responses. β-blockers differ in their adrenoceptor subtype affinity, lipophilicity, and α-blocking capabilities. The history of β-blocker development began with the prototype, dichloroisoprenaline, which exhibited partial agonist activity. As a result, propranolol was developed as a pure antagonist but nonselective agent, paving the way...
Antihypertensive Drugs: Types of β-Blockers01:28

Antihypertensive Drugs: Types of β-Blockers

β receptors are classified into three subclasses: β1, β2, and β3. β1 receptors are primarily located in the heart and kidneys. When they get activated, they increase heart rate, contractility, and renin release. This process enhances blood pressure and aids in stress management. In contrast, β2 receptors are situated mainly in the lungs, blood vessels, and skeletal muscles. Upon activation, they trigger smooth muscle relaxation, causing bronchodilation and vasodilation. This widens airways and...
Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action01:17

Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action

Nondepolarizing neuromuscular blockers induce paralysis by competitively blocking nicotinic acetylcholine receptors at the muscle end plate. Examples include pancuronium, mivacurium, vecuronium, and rocuronium. These quaternary ammonium derivatives are administered intravenously, are poorly absorbed, and are excreted via the kidneys.
Competitive antagonists prevent acetylcholine from binding to its receptor, inhibiting membrane depolarization. Without conformational changes or intrinsic...
Adrenergic Receptors: β Subtype01:26

Adrenergic Receptors: β Subtype

β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...

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Cellular Membrane Affinity Chromatography Columns to Identify Specialized Plant Metabolites Interacting with Immobilized Tropomyosin Kinase Receptor B
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Small molecule DnaK modulators targeting the beta-domain.

Jason Cellitti1, Ziming Zhang, Si Wang

  • 1Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

Chemical Biology & Drug Design
|August 22, 2009
PubMed
Summary

Researchers identified novel small molecules that inhibit bacterial growth by targeting the essential DnaK chaperone. These compounds show promise as new antimicrobial drug candidates against pathogens like Yersinia pseudotuberculosis.

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Published on: August 16, 2018

Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • The bacterial molecular chaperone DnaK is crucial for pathogen survival in host environments.
  • DnaK is a potential drug target, but effective small molecule inhibitors are lacking.
  • Existing inhibitors, such as antimicrobial peptides, have limitations.

Purpose of the Study:

  • To screen for small molecules that bind to the DnaK substrate-binding domain.
  • To identify novel inhibitors of bacterial growth targeting DnaK.
  • To evaluate the efficacy of identified compounds against bacterial pathogens.

Main Methods:

  • Screening of small molecule libraries for DnaK interaction.
  • Synthesis and characterization of promising hit compounds and analogs.
  • Assays to determine binding affinity and bacterial growth inhibition.

Main Results:

  • Identification of small molecules with submicromolar binding affinity for DnaK.
  • Demonstration of potent inhibition of Yersinia pseudotuberculosis growth by these compounds.
  • Compounds showed superior efficacy compared to previously known antimicrobial peptides.

Conclusions:

  • Novel small molecules effectively inhibit bacterial DnaK.
  • These compounds represent promising leads for developing new antibacterial therapeutics.
  • Targeting DnaK offers a viable strategy against bacterial pathogens.