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Factors Affecting Protein-Drug Binding: Drug Interactions01:23

Factors Affecting Protein-Drug Binding: Drug Interactions

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Drug interactions are a critical aspect of pharmacology and can occur when two or more drugs compete for the same binding site. This competition can result in one drug displacing another, altering the effect of the displaced drug. Drug interactions are complex processes that rely heavily on how much of the displacer drug is present and how strongly it can bind to the same sites as the displaced drug.
Displacement interactions can have varying outcomes, ranging from toxicity to virtually...
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Pharmacokinetics: Drug–Drug Interactions01:25

Pharmacokinetics: Drug–Drug Interactions

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Drug interactions occur when the pharmacological effect of one drug is altered by another substance, either enhancing or diminishing its activity. The drug whose activity is altered is known as the object drug, and the substance causing the alteration is called the agent drug or the precipitant. The net effects of these interactions are mostly undesirable, leading to decreased effectiveness or increased adverse effects. In rare cases, interactions can be beneficial, such as the enhanced...
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Drug toxicity: Drug–Drug Interaction01:30

Drug toxicity: Drug–Drug Interaction

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Drug–drug interactions can precipitate toxicity through multiple mechanisms. Absorption interactions alter how drugs enter the body, exemplified when ranitidine increases the absorption of basic drugs, while cholestyramine decreases the levels of propranolol. Protein binding interactions occur when drugs share the same binding sites on plasma proteins. Drugs like aspirin and warfarin, when bound in excess, can lead to increased free drug concentrations, enhancing the potential for...
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Protein-Drug Binding: Mechanism and Kinetics01:16

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Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
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Inhibition of Cdk Activity02:34

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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

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Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
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Sunitinib: from charge-density studies to interaction with proteins.

Maura Malińska1, Katarzyna N Jarzembska1, Anna M Goral1

  • 1Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.

Acta Crystallographica. Section D, Biological Crystallography
|May 13, 2014
PubMed
Summary

Sunitinib malate, a tyrosine kinase inhibitor, exhibits a consistent interaction pattern with various protein kinases. Its ability to adjust conformation enhances electrostatic interactions, contributing to its broad-spectrum efficacy in treating diseases.

Keywords:
QTAIMelectrostatic potentialinteraction energyprotein kinases

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Protein kinases are crucial drug targets for numerous diseases.
  • Sunitinib malate, a type I tyrosine kinase inhibitor, gained drug approval in 2006.
  • Understanding drug-target interactions at a molecular level is vital for drug development.

Purpose of the Study:

  • To conduct a comprehensive analysis of sunitinib malate's crystal structure.
  • To investigate the structural complexes of sunitinib with various protein kinases.
  • To elucidate the charge-density distribution and intermolecular interactions of sunitinib in its crystalline form and in complex with kinases.

Main Methods:

  • High-resolution single-crystal X-ray diffraction measurements.
  • Aspherical atom crystallographic databases for charge density reconstruction.
  • Hirshfeld surface analysis and topological studies of intermolecular interactions.

Main Results:

  • The crystal structure of sunitinib malate reveals interaction patterns similar to those in protein kinase binding pockets.
  • Sunitinib forms nine conserved bond paths, including hydrogen bonds and C-H···O/π contacts, with kinases like VEGRF2, CDK2, G2, KIT, and IT.
  • Sunitinib demonstrates consistent electrostatic interaction energy with studied proteins and adapts its conformation to optimize binding, particularly hydrogen bonds.

Conclusions:

  • Sunitinib's binding interactions within protein kinase pockets are conserved between its crystal structure and drug-target complexes.
  • The drug's conformational flexibility allows it to enhance electrostatic interactions, such as hydrogen bonds, within kinase binding sites.
  • These adaptable binding characteristics likely contribute to sunitinib's broad-spectrum activity as a kinase inhibitor.