title: Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors.
abstract: Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors.
authors.affiliation: Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, Università degli Studi di Genova, Viale Benedetto XV 3, 16132, Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Pasqualina
authors.initials: P
authors.lastname: D'Ursi
authors.forename: Marco
authors.initials: M
authors.lastname: Moscatelli
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orro
authors.forename: Chiara
authors.initials: C
authors.lastname: Rotolo
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry; D016415:Sequence Alignment
chemical_list: D010726:Phosphodiesterase Inhibitors; D011744:Pyrimidinones; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C406737:PDE11A protein, human; C517381:PDE5A protein, human
keywords: 3D-model; Graphical Processing Unit computing; catalytic site; homology modeling; molecular docking; molecular dynamic simulations; phosphodiesterase 11; selectivity