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Exploring structure-promiscuity relationships using dual-site promiscuity cliffs and corresponding single-site

Huabin Hu1, Jürgen Bajorath1

  • 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
PubMed
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.

Keywords:
Analog seriesCompound promiscuityComputational analysisDual-site promiscuity cliffsKinase inhibitorsSingle-site analogsStructure-promiscuity relationships

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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.