Many approved drugs have bioactive analogs with different target annotations
Ye Hu1, Eugen Lounkine, Jürgen Bajorath
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, D-53113, Bonn, Germany.
The AAPS Journal
|May 30, 2014
Summary
Structural analysis reveals that drug analogs often interact with unexpected targets, suggesting new therapeutic hypotheses and highlighting potential database and drug repositioning issues.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Bioinformatics
Background:
- Approved drugs and bioactive compounds often share close structural relationships.
- Understanding these relationships is crucial for drug discovery and development.
- Existing databases like ChEMBL and DrugBank contain valuable drug and target information.
Purpose of the Study:
- To systematically assess structural relationships between approved drugs and bioactive compounds.
- To identify potential alternative drug targets using matched molecular pair analysis.
- To investigate discrepancies between known drug targets and those of their structural analogs.
Main Methods:
- Utilized matched molecular pair analysis to identify structural analogs.
- Assembled drug target information from ChEMBL and DrugBank databases.
- Compared target profiles of drugs with those of their identified structural analogs.
Main Results:
- Identified multiple structural analogs for many approved drugs.
- Observed that these analogs were often active against different targets, some related and some unrelated to known drug targets.
- Discovered surprising discrepancies between reported drug targets and the targets of close structural analogs.
Conclusions:
- Close structural relationships can facilitate the formulation of hypotheses for alternative drug targets.
- These structure-target relationships may be overlooked during drug development focused on primary targets.
- Findings raise important questions about the accuracy of database content and the strategies for drug repositioning.
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