Related Experiment Video
Updated: May 30, 2026
05:10
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
Identify drug repurposing candidates by mining the protein data bank
Fabrice Moriaud1, Stéphane B Richard, Stewart A Adcock
1MEDIT SA, 2 rue du Belvedere, 91120 Palaiseau, France. fmoriaud@medit.fr
Briefings in Bioinformatics
|July 20, 2011
Summary
Computational methods predict drug off-targets by comparing 3D protein structures. This approach identifies potential drug repurposing opportunities and undesired side effects by finding similar binding sites in the Protein Data Bank (PDB).
Area of Science:
- Computational chemistry
- Structural biology
- Drug discovery
Background:
- Predicting off-target effects computationally is crucial in early-stage drug discovery.
- Identifying similar binding sites across protein structures can indicate potential target hopping and drug repurposing.
- Existing methods often rely on predefined pocket detection, limiting comprehensive analysis.
Purpose of the Study:
- To present a novel computational method for predicting drug off-targets and enabling drug repurposing.
- To leverage full 3D structure comparisons within the Protein Data Bank (PDB) for broader analysis.
- To explore the potential for both drug-sized and fragment repurposing based on structural similarities.
Main Methods:
- Utilizing a computational method based on full 3D structure comparisons of proteins.
- Searching the entire surface of proteins in the PDB, not limited to pre-defined pockets.
- Applying the method to identify repurposing of tadalafil and mining the PDB for kinase hinge region similarities.
Main Results:
- The method successfully reproduced the known repurposing of tadalafil from PDE5A to PDE4A.
- Searching for local protein similarities yielded more hits than whole binding site comparisons, suggesting higher likelihood of fragment repurposing.
- Experimentally validated examples, biotin carboxylase and synapsin, were retrieved when mining for kinase hinge region similarities.
- The approach detected the protein kinase hinge motif in the HIV-RT allosteric site, demonstrating druggable site identification.
Conclusions:
- The developed computational method offers a powerful tool for predicting off-target effects and identifying drug repurposing candidates.
- Comparing full 3D protein structures and surfaces enhances the discovery of both drug and fragment repurposing opportunities.
- This approach extends beyond binding site similarity to detect druggable sites, broadening its applicability in drug discovery and development.
Related Concept Videos
01:26Drug Discovery: Overview
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
02:04Protein-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...
02:26Protein Networks
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...