title: Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics.
abstract: Alzheimer's disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D-MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in-house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors.
authors.affiliation: Institute for Biomedical Technologies e National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090, Segrate (MI, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: D'Ursi
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132, Genova (GE, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Guariento
authors.affiliation: Institute for Biomedical Technologies e National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090, Segrate (MI, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Trombetti
authors.affiliation: Institute for Biomedical Technologies e National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090, Segrate (MI, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orro
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132, Genova (GE, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Institute for Biomedical Technologies e National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090, Segrate (MI, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132, Genova (GE, Italy . fossap@unige.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132, Genova (GE, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
mesh_terms: D001665:Binding Sites / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human
keywords: PDE4; PDE4D selective inhibitors; Phosphodiesterases; docking; molecular dynamics