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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.
Chem Biol Drug Des. 2013 Dec; 82(6):718-31.CB

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Cichero E
Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, Università degli Studi di Genova, Viale Benedetto XV 3, 16132, Genova, Italy.
D'Ursi P
No affiliation info available
Moscatelli M
No affiliation info available
Bruno O
No affiliation info available
Orro A
No affiliation info available
Rotolo C
No affiliation info available
Milanesi L
No affiliation info available
Fossa P
No affiliation info available

MeSH

3',5'-Cyclic-GMP PhosphodiesterasesAmino Acid SequenceBinding SitesCatalytic DomainCrystallography, X-RayCyclic Nucleotide Phosphodiesterases, Type 5Drug DesignHumansMolecular Docking SimulationMolecular Dynamics SimulationMolecular Sequence DataPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesProtein BindingPyrimidinonesSequence Alignment

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23865680

Citation

Cichero, Elena, et al. "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." Chemical Biology & Drug Design, vol. 82, no. 6, 2013, pp. 718-31.
Cichero E, D'Ursi P, Moscatelli M, et al. 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. Chem Biol Drug Des. 2013;82(6):718-31.
Cichero, E., D'Ursi, P., Moscatelli, M., Bruno, O., Orro, A., Rotolo, C., Milanesi, L., & Fossa, P. (2013). 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. Chemical Biology & Drug Design, 82(6), 718-31. https://doi.org/10.1111/cbdd.12193
Cichero E, et al. 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. Chem Biol Drug Des. 2013;82(6):718-31. PubMed PMID: 23865680.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Cichero,Elena, AU - D'Ursi,Pasqualina, AU - Moscatelli,Marco, AU - Bruno,Olga, AU - Orro,Alessandro, AU - Rotolo,Chiara, AU - Milanesi,Luciano, AU - Fossa,Paola, Y1 - 2013/08/26/ PY - 2013/01/17/received PY - 2013/06/14/revised PY - 2013/07/09/accepted PY - 2013/7/20/entrez PY - 2013/7/20/pubmed PY - 2014/6/17/medline KW - 3D-model KW - Graphical Processing Unit computing KW - catalytic site KW - homology modeling KW - molecular docking KW - molecular dynamic simulations KW - phosphodiesterase 11 KW - selectivity SP - 718 EP - 31 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 82 IS - 6 N2 - 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. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/23865680/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_ DB - PRIME DP - Unbound Medicine ER -