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

Area of Science:

• Structural biology
• Medicinal chemistry
• Drug discovery

Background:

• Phosphodiesterases (PDEs) are crucial drug targets.
• Understanding PDE-ligand interactions is vital for drug development.
• A large number of PDE crystal structures are available in the Protein Data Bank (PDB).

Purpose of the Study:

• To systematically analyze PDE catalytic domain crystal structures and PDE-ligand interactions.
• To identify subtype-specific interaction features and classify ligands based on binding modes.
• To provide insights for scaffold hopping and ligand design in drug discovery.

Main Methods:

• Systematic structural alignment of 220 PDE catalytic domain crystal structures from the PDB.
• Analysis of PDE-ligand interaction fingerprints (IFPs) using 57 conserved binding site residues.
• Substructure analysis of cocrystallized PDE ligands and ChEMBL database compounds.

Main Results:

• Identification of conserved and subtype-specific PDE-ligand interaction hot spots.
• Classification of ligands based on distinct binding modes within PDE catalytic domains.
• Development of a PDE structure and ligand interaction annotated (PDEStrIAn) database.

Conclusions:

• Systematic analysis of PDE structures and interactions provides valuable insights for drug design.
• Understanding conserved and selective interaction features aids in accommodating diverse chemical scaffolds.
• The findings offer a toolbox for scaffold hopping and improved PDE-targeted drug discovery.