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Analyzing Protein Architectures and Protein-Ligand Complexes by Integrative Structural Mass Spectrometry
Published on: October 15, 2018
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X-ray Structures of Target-Ligand Complexes Containing Compounds with Assay Interference Potential.
Erik Gilberg1,2, Michael Gütschow2, Jürgen Bajorath1
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstr. 2, D-53113 Bonn, Germany.
Journal of Medicinal Chemistry
|January 13, 2018
Summary
Pan assay interference compounds (PAINS) can cause artifacts in biological assays. Structural analysis reveals PAINS motifs in many protein-ligand complexes, highlighting their potential for both specific interactions and assay interference.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Biochemistry
Background:
- Pan assay interference compounds (PAINS) are known to cause artifacts in biological assays.
- PAINS-defining substructures are often found within larger molecules.
- Understanding the structural basis of PAINS is crucial for reliable drug discovery.
Purpose of the Study:
- To systematically examine X-ray structures of protein-ligand complexes for the presence of PAINS motifs.
- To investigate the relationship between PAINS substructures, ligand-target interactions, and potential assay artifacts.
- To categorize PAINS-containing ligands based on structural data for improved interpretation.
Main Methods:
- Systematic analysis of 2874 X-ray structures of protein-ligand complexes.
- Identification and classification of ligands containing PAINS substructures.
- Examination of ligand-target interactions and potential reactivity using crystallographic data.
Main Results:
- 1107 unique ligands with PAINS substructures, belonging to 70 different classes, were identified across the analyzed structures.
- Common PAINS motifs detected include quinones, catechols, and Mannich bases.
- Structural data indicated that ligand reactivity can contribute to complex formation, and specific interactions are not mutually exclusive with assay interference.
Conclusions:
- Structural analysis provides valuable insights into the behavior of PAINS compounds.
- Distinguishing between specific interactions and assay artifacts is possible with careful consideration of structural data.
- Integrating crystallographic information enhances the analysis and interpretation of interference compounds in drug discovery.
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