title: Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
abstract: Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
authors.affiliation: deCODE biostructures, Bainbridge Island, Washington, USA. aburgin@embios.com
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Pam
authors.initials: P
authors.lastname: Witte
authors.forename: Bart L
authors.initials: BL
authors.lastname: Staker
authors.forename: Jon M
authors.initials: JM
authors.lastname: Bjornsson
authors.forename: Margret
authors.initials: M
authors.lastname: Thorsteinsdottir
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hrafnsdottir
authors.forename: Timothy
authors.initials: T
authors.lastname: Hagen
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Stewart
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001681:Biological Assay; D020134:Catalytic Domain; D002460:Cell Line; D003071:Cognition / Q000187:drug effects*; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000188:drug therapy
chemical_list: D001559:Benzhydryl Compounds; C000596953:D159687; D010671:Phenylurea Compounds; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4