1. Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds
- Author
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Luca Mollica, Egidio Aiolfi, Olga Bruno, Tommaso Prosdocimi, Silvana Alfei, Marta S. Semrau, Paola Storici, Andrea Cavalli, Stefano Donini, Emilio Parisini, Chiara Brullo, A.P. Lucarelli, Prosdocimi, Tommaso, Mollica, Luca, Donini, Stefano, Semrau, Marta S., Lucarelli, Anna Paola, Aiolfi, Egidio, Cavalli, Andrea, Storici, Paola, Alfei, Silvana, Brullo, Chiara, Bruno, Olga, and Parisini, Emilio
- Subjects
0301 basic medicine ,Gene isoform ,Stereochemistry ,Context (language use) ,Ligand ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Ligands ,Biochemistry ,03 medical and health sciences ,Molecular dynamics ,Structure-Activity Relationship ,0302 clinical medicine ,Memory ,Catalytic Domain ,Hydrolase ,Structure–activity relationship ,Animals ,Humans ,chemistry.chemical_classification ,Animal ,Phosphodiesterase ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,030104 developmental biology ,Enzyme ,chemistry ,Phosphodiesterase 4 Inhibitor ,Phosphodiesterase 4 Inhibitors ,Rolipram ,030217 neurology & neurosurgery ,Human - Abstract
Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.
- Published
- 2018