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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...
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...
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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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
08:49

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

Published on: June 20, 2025

Protein-ligand docking with multiple flexible side chains.

Yong Zhao1, Michel F Sanner

  • 1Department of Molecular Biology, TPC26, The Scripps Research Institute, 10550 North Torrey Pine Rd, La Jolla, CA, 92037-1000, USA. yongzhao@scripps.edu

Journal of Computer-Aided Molecular Design
|November 24, 2007
PubMed
Summary

Failed molecular docking simulations can be improved by accounting for receptor side chain flexibility. This study identifies key flexible side chains, enhancing docking accuracy for 22 out of 25 complexes using FLIPDock software.

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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Published on: June 23, 2026

Area of Science:

  • Computational chemistry
  • Molecular modeling
  • Drug discovery

Background:

  • Cross-docking simulations are crucial for predicting ligand-receptor interactions.
  • A significant number of docking experiments fail, limiting their predictive power.
  • Receptor flexibility, particularly in side chains near the active site, is often overlooked.

Purpose of the Study:

  • To analyze failed cross-docking experiments and identify causes related to receptor conformational changes.
  • To develop and validate a method for incorporating side chain flexibility into docking calculations.
  • To improve the success rate of molecular docking for drug discovery.

Main Methods:

  • Analysis of 33 failed cross-docking experiments across four receptors (cAPK, CDK2, Ricin, HIVp).
  • Identification of flexible side chains by superimposing receptors and analyzing steric clashes between ligands and side chains.
  • Implementation of rotameric conformations for selected side chains within the FLIPDock software.
  • Exploration of distance-based methods (molecular surface, Euclidean distance) for selecting flexible side chains.
  • Application of geometric constraints from interaction networks to rank and select side chains.

Main Results:

  • 25 out of 33 failed dockings were attributed to conformational changes in active site side chains.
  • Making identified side chains flexible enabled successful cross-docking for 19 complexes (RMSD < 2.0 A).
  • Methods for selecting flexible side chains were evaluated, with molecular surface growing being more efficient but often selecting too many residues.
  • Incorporating geometric constraints to rank and select top side chains led to a success rate of 22 out of 25 complexes.

Conclusions:

  • Receptor side chain flexibility is a critical factor in the success of molecular docking.
  • FLIPDock, with flexible side chains, significantly improves docking accuracy.
  • Optimized selection strategies for flexible side chains are essential for robust docking predictions.