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Exploring structure-promiscuity relationships using dual-site promiscuity cliffs and corresponding single-site
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Endenicher Allee 19c, D-53115 Bonn, Germany.
Bioorganic & Medicinal Chemistry
|December 11, 2019
Summary
New promiscuity cliffs (PCs) analysis reveals how small chemical changes impact compound multi-target activity. This method helps understand structure-promiscuity relationships and guides drug discovery efforts.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Drug Discovery
Background:
- Compound promiscuity, or multi-target activity, is crucial in drug discovery.
- Promiscuity cliffs (PCs) identify structural analogs with differing target profiles.
- Existing PC methods are limited to single-site chemical modifications.
Purpose of the Study:
- To introduce and analyze PCs with multiple substitution sites.
- To develop an extended data structure for dual-site PCs (dsPCs).
- To explore structure-promiscuity relationships and potential experimental causes for promiscuity differences.
Main Methods:
- Application of the matched molecular pair formalism to identify multi-site PCs.
- Generation of an extended data structure for dsPCs, including single-site analogs.
- Analysis of a large dataset of protein kinase inhibitors.
Main Results:
- Multi-site PCs, particularly dsPCs, were identified and characterized.
- The extended dsPC format provides intuitive chemical interpretation.
- The analog quartet offers rich information on structure-promiscuity relationships and potential experimental artifacts.
Conclusions:
- The newly introduced multi-site PC format enhances the exploration of compound promiscuity.
- This approach aids in understanding the interplay of chemical modifications on target activity.
- It facilitates the formulation of testable hypotheses for analog development in medicinal chemistry.
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