PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design

A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE–ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE–...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-08, Vol.59 (15), p.7029-7065
Main Authors: Jansen, Chimed, Kooistra, Albert J, Kanev, Georgi K, Leurs, Rob, de Esch, Iwan J. P, de Graaf, Chris
Format: Article
Language:English
Subjects:
Databases, Protein
Dose-Response Relationship, Drug
Drug Design
Humans
Ligands
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors - chemistry
Phosphodiesterase Inhibitors - pharmacology
Phosphoric Diester Hydrolases - chemistry
Phosphoric Diester Hydrolases - metabolism
Structure-Activity Relationship
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Summary:A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE–ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE–ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE–ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01813