PDEStrIAn: A phosphodiesterase structure and ligan interaction annotated database as a tool for structure-based drug design.

C.J.W. Jansen, A.J. Kooistra, G.K. Kanev, R. Leurs, I.J.P. de Esch, C. de Graaf

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)7029-7065
JournalJournal of Medicinal Chemistry
Volume59
Issue number15
DOIs
Publication statusPublished - 2016

Fingerprint

Drug Design
Phosphoric Diester Hydrolases
Databases
Ligands
Dermatoglyphics
Drug Discovery
Catalytic Domain
Binding Sites

Cite this

@article{4fbe05eb49ab4e58811365751a7e03d7,
title = "PDEStrIAn: A phosphodiesterase structure and ligan interaction annotated database as a tool for structure-based drug design.",
abstract = "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.",
author = "C.J.W. Jansen and A.J. Kooistra and G.K. Kanev and R. Leurs and {de Esch}, I.J.P. and {de Graaf}, C.",
year = "2016",
doi = "10.1021/acs.jmedchem.5b01813",
language = "English",
volume = "59",
pages = "7029--7065",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "15",

}

PDEStrIAn: A phosphodiesterase structure and ligan interaction annotated database as a tool for structure-based drug design. / Jansen, C.J.W.; Kooistra, A.J.; Kanev, G.K.; Leurs, R.; de Esch, I.J.P.; de Graaf, C.

In: Journal of Medicinal Chemistry, Vol. 59, No. 15, 2016, p. 7029-7065.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - PDEStrIAn: A phosphodiesterase structure and ligan interaction annotated database as a tool for structure-based drug design.

AU - Jansen, C.J.W.

AU - Kooistra, A.J.

AU - Kanev, G.K.

AU - Leurs, R.

AU - de Esch, I.J.P.

AU - de Graaf, C.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.5b01813

DO - 10.1021/acs.jmedchem.5b01813

M3 - Article

VL - 59

SP - 7029

EP - 7065

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -