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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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...
Ligand Binding Sites02:40

Ligand Binding Sites

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...
Conserved Binding Sites01:49

Conserved Binding Sites

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.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Ligand Binding and Linkage00:49

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

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...
Protein-protein Interfaces02:04

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...

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Protein-ligand docking against non-native protein conformers.

Marcel L Verdonk1, Paul N Mortenson, Richard J Hall

  • 1Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom. m.verdonk@astex-therapeutics.com

Journal of Chemical Information and Modeling
|October 29, 2008
PubMed
Summary

Protein-ligand docking performance significantly decreases with non-native protein conformations. Docking against similar ligands or multiple non-native structures can recover performance, highlighting the need for realistic validation sets.

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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

Published on: June 20, 2025

Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Protein-ligand docking protocols are typically validated against native protein conformations.
  • Real-world applications often involve docking ligands into non-native protein structures (e.g., apo or different complexes).
  • This discrepancy between validation and application settings can impact docking accuracy.

Purpose of the Study:

  • To develop and utilize an extensive test set for assessing protein-ligand docking performance against non-native protein conformations.
  • To quantify the performance drop-off in docking when using non-native protein structures compared to native ones.
  • To investigate strategies for improving docking performance in non-native scenarios.

Main Methods:

  • Construction of the Astex Non-native Set, comprising 1112 non-native structures for 65 drug targets, based on the Astex Diverse Set.
  • Utilizing the GOLD protein-ligand docking program to evaluate docking performance on both native and non-native structure sets.
  • Analysis of docking performance (top-ranked solution accuracy) and sampling performance (any correct solution).

Main Results:

  • Docking performance dropped from approximately 80% for native docking to 61% for non-native docking.
  • Sampling performance decreased from 91% for native to 72% for non-native docking.
  • Larger protein conformational changes significantly degraded performance, while docking against similar ligands or multiple non-native structures improved results.

Conclusions:

  • Current protein-ligand docking validation methods may overestimate performance due to the use of native protein conformations.
  • Docking against non-native protein conformations presents a significant challenge, necessitating the use of more realistic test sets.
  • Strategies like ensemble docking or docking against similar ligand complexes can mitigate performance loss in non-native scenarios.