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Related Concept Videos

Gap Junctions01:37

Gap Junctions

Multicellular organisms employ a variety of ways for cells to communicate with each other. Gap junctions are specialized proteins that form pores between neighboring cells in animals, connecting the cytoplasm between the two, and allowing for the exchange of molecules and ions. They are found in a wide range of invertebrate and vertebrate species, mediate numerous functions including cell differentiation and development, and are associated with numerous human diseases, including cardiac and...
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Ligand Binding and Linkage

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 the...
Ligand Binding and Linkage00:49

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Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that include the...
Gap Junctions01:27

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The cytoplasm of adjacent animal cells can exchange small molecules, ions, and secondary messengers via the communication channels which form the gap junctions. These junctions comprise a few hundred to thousands of molecular channels, each made of two halves, called the connexon hemichannel. A connexon is a hexamer of six transmembrane connexin proteins, which assemble radially, thus forming a pore or channel in the center. One connexon hemichannel docks with a corresponding connexon on the...
Ligand-gated Ion Channels01:19

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Insertion of Flexible Neural Probes Using Rigid Stiffeners Attached with Biodissolvable Adhesive
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Representing receptor flexibility in ligand docking through relevant normal modes.

Claudio N Cavasotto1, Julio A Kovacs, Ruben A Abagyan

  • 1Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, California 92037, USA. claudio@molsoft.com

Journal of the American Chemical Society
|June 30, 2005
PubMed
Summary
This summary is machine-generated.

This study introduces a novel normal-mode method to model receptor flexibility in drug discovery. The approach enhances ligand docking accuracy and improves virtual screening by generating diverse receptor conformations.

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Area of Science:

  • Computational Biology
  • Structural Biology
  • Drug Discovery

Background:

  • Ligand-receptor interactions are crucial in drug discovery.
  • Existing docking methods often struggle to accurately represent receptor flexibility.
  • Protein flexibility, especially in binding pockets, significantly impacts ligand binding affinity.

Purpose of the Study:

  • To develop a normal-mode-based methodology for incorporating receptor flexibility into ligand docking and virtual screening.
  • To address the limitations of existing methods in representing complex protein deformations.
  • To improve the accuracy and efficiency of structure-based drug discovery tools.

Main Methods:

  • Introduced a relevance measure for normal modes to identify key flexibility modes.
  • Generated an ensemble of receptor conformations by perturbing along relevant normal modes.
  • Employed full flexible docking and receptor ensemble docking for virtual screening.
  • Evaluated the method on cAMP-dependent protein kinase holo and apo structures.

Main Results:

  • The method effectively captures loop flexibility in cAMP-dependent protein kinase using a limited number of low-frequency modes.
  • Docking accuracy improved, with ligands achieving within 1.5 Å of target structures.
  • Virtual screening performance was enhanced, indicated by an improved enrichment factor.
  • Demonstrated improved discrimination between binders and non-binders.

Conclusions:

  • The developed normal-mode approach systematically integrates flexible ligand-flexible receptor docking.
  • This methodology represents a significant advancement for structure-based drug discovery.
  • The approach offers a more realistic modeling of protein flexibility in computational screening.