7B9H

Crystal structure of the PDE4D catalytic domain in complex with GEBR-42a

Summary for 7B9H

• Entry DOI: 10.2210/pdb7b9h/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase 4d, inhibitor, complex, gebr, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 82094.00

Authors

Torretta, A.,Abbate, S.,Parisini, E. (deposition date: 2020-12-14, release date: 2021-06-30, Last modification date: 2024-01-31)

Primary citation

Brullo, C.,Rapetti, F.,Abbate, S.,Prosdocimi, T.,Torretta, A.,Semrau, M.,Massa, M.,Alfei, S.,Storici, P.,Parisini, E.,Bruno, O.
Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.
Eur.J.Med.Chem., 223:113638-113638, 2021

PubMed Abstract: Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme.

PubMed: 34171658
DOI: 10.1016/j.ejmech.2021.113638

Experimental method

X-RAY DIFFRACTION (1.5 Å)