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

TY - JOUR

T1 - PDEStrIAn

T2 - A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design

AU - Jansen, Chimed

AU - Kooistra, Albert J.

AU - Kanev, Georgi K.

AU - Leurs, Rob

AU - De Esch, Iwan J.P.

AU - De Graaf, Chris

PY - 2016/8/11

Y1 - 2016/8/11

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.

UR - http://www.scopus.com/inward/record.url?scp=84982084049&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b01813

DO - 10.1021/acs.jmedchem.5b01813

M3 - Review

AN - SCOPUS:84982084049

SN - 0022-2623

VL - 59

SP - 7029

EP - 7065

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -