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Ligand Binding Sites02:40

Ligand Binding Sites

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
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Identification of Novel Smoothened Ligands Using Structure-Based Docking.

Celine Lacroix1, Inbar Fish2,3, Hayarpi Torosyan2

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Summary

Researchers identified novel Smoothened antagonists to overcome drug resistance in Hedgehog pathway cancers. These new compounds show efficacy against resistant mutations, offering hope for improved cancer treatments.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • The seven transmembrane protein Smoothened is crucial for Hedgehog signaling in development and homeostasis.
  • Hedgehog pathway activation drives cancers like basal cell carcinoma and medulloblastoma, with Smoothened inhibitors in clinical use.
  • Drug resistance to current Smoothened inhibitors limits their therapeutic efficacy.

Purpose of the Study:

  • To discover novel Smoothened ligands with new chemotypes to combat drug resistance.
  • To leverage Smoothened crystal structures for structure-based drug discovery.
  • To identify compounds effective against Smoothened mutations conferring clinical resistance.

Main Methods:

  • Docking of 3.2 million lead-like molecules against Smoothened structure.
  • Experimental testing of high-ranking docked compounds.
  • Analog screening to identify more potent molecules.
  • Testing efficacy against the clinically resistant D473H Smoothened mutant.

Main Results:

  • Four novel Smoothened antagonists from three chemotypes were identified with IC50 < 50 μM.
  • Six additional analogs were found with low micromolar IC50 values.
  • One potent antagonist demonstrated efficacy against the D473H resistant mutant.

Conclusions:

  • Structure-based drug discovery against Smoothened can yield novel antagonists.
  • New chemotypes are effective against Smoothened and can overcome resistance mechanisms.
  • Identified compounds offer potential for developing next-generation cancer therapeutics targeting the Hedgehog pathway.