PDBsum entry 4nw7

Hydrolase/hydrolase inhibitor

PDB id: 4nw7

Contents

Protein chain

344 a.a.

Ligands

2O5

EDO ×6

Metals

_ZN

_MG

_NA

Waters ×193

References listed in PDB file

Key reference

• Title: Discovery of triazines as selective pde4b versus pde4d inhibitors.
• Authors: T.J.Hagen, X.Mo, A.B.Burgin, D.Fox, Z.Zhang, M.E.Gurney.
• Ref.: Bioorg Med Chem Lett, 2014, 24, 4031-4034. [DOI no: 10.1016/j.bmcl.2014.06.002]
• PubMed id: 24998378

Abstract

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.