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Related Concept Videos

Factors Affecting Protein-Drug Binding: Drug-Related Factors01:18

Factors Affecting Protein-Drug Binding: Drug-Related Factors

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Drug binding to proteins is a complex phenomenon influenced by various drug-related factors, each playing a significant role in the interaction between drugs and proteins within the body.
One crucial factor in drug-protein binding is the drug's lipophilicity or its affinity for fat. More lipophilic drugs tend to have higher binding extents. For example, highly lipophilic drugs like cloxacillin exhibit substantial protein binding, with as much as 95% of the drug binding to proteins. In...
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Factors Affecting Protein-Drug Binding: Protein-Related Factors01:20

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Drug binding to proteins is a key aspect of pharmacokinetics and can influence a drug's distribution, absorption, and elimination in the body. Several factors, including the drug's physiochemical properties, protein concentration, disease states, and the number of binding sites on the protein, influence this process.
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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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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.
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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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Related Experiment Video

Updated: Mar 21, 2026

Microfluidic On-chip Capture-cycloaddition Reaction to Reversibly Immobilize Small Molecules or Multi-component Structures for Biosensor Applications
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Decoding structural and dynamic determinants of Tropifexor-FXR binding: A comprehensive computational analysis.

Suman Sinha1, Ram Kumar1

  • 1Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.

Journal of Molecular Graphics & Modelling
|March 19, 2026
PubMed
Summary
This summary is machine-generated.

Tropifexor, a selective Farnesoid X receptor (FXR) agonist, demonstrates high binding affinity and selectivity through unique interactions. These findings provide a blueprint for developing improved FXR modulators for liver diseases.

Keywords:
Cholestatic liver diseasesMolecular dynamics simulationsNuclear receptorTropifexorUnbinding pathways

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Farnesoid X receptor (FXR) is a key therapeutic target for metabolic diseases like non-alcoholic fatty liver disease, diabetes, and atherosclerosis.
  • Tropifexor is a selective FXR agonist with demonstrated efficacy in cholestatic liver diseases and non-alcoholic steatohepatitis.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying Tropifexor's binding affinity and selectivity for FXR.
  • To elucidate the structural dynamics and activation pathways of the FXR-Tropifexor complex.

Main Methods:

  • Comprehensive structural analyses using molecular dynamics (MD) simulations.
  • Unbiased MD and Weighted-Ensemble Metadynamics simulations of the FXR-Tropifexor complex.
  • Analysis of ligand-induced receptor conformational changes and unbinding pathways.

Main Results:

  • Tropifexor achieves high binding affinity and selectivity via π-sulphur, π-π, and carbon-π interactions, complementing hydrogen bonding.
  • A conformational wedge mechanism, involving binding pocket expansion and helical fluctuations, stabilizes and activates FXR.
  • Two distinct unbinding pathways were identified, with the predominant one promoting prolonged receptor activation due to significant energy barriers.

Conclusions:

  • The study reveals the detailed structural basis for Tropifexor's potent FXR agonism.
  • These findings offer a rational design strategy for next-generation FXR modulators with improved therapeutic profiles.