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Crystal Structure of Human Phosphodiesterase 3B:  Atomic Basis for Substrate and Inhibitor Specificity

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Departments of Medicinal Chemistry and Metabolic Disorders, Merck & Co., Rahway, New Jersey 07065, and MRL San Diego Neuroscience Center, San Diego, California 92121
Cite this: Biochemistry 2004, 43, 20, 6091–6100
Publication Date (Web):April 27, 2004
Copyright © 2004 American Chemical Society

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    Phosphodiesterases (PDEs) are enzymes that modulate cyclic nucleotide signaling and as such are clinical targets for a range of disorders including congestive heart failure, erectile dysfunction, and inflammation. The PDE3 family comprises two highly homologous subtypes expressed in different tissues, and inhibitors of this family have been shown to increase lipolysis in adipocytes. A specific PDE3B (the lipocyte-localized subtype) inhibitor would be a very useful tool to evaluate the effects of PDE3 inhibition on lipolysis and metabolic rate and might become a novel tool for treatment of obesity. We report here the three-dimensional structures of the catalytic domain of human PDE3B in complex with a generic PDE inhibitor and a novel PDE3 selective inhibitor. These structures explain the dual cAMP/cGMP binding capabilities of PDE3, provide the molecular basis for inhibitor specificity, and can supply a valid platform for the design of improved compounds.

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     The facilities at IMCA-CAT are supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Illinois Institute of Technology (IIT), executed through IIT's Center for Synchrotron Radiation Research and Instrumentation. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38.


     To whom correspondence should be addressed. Tel:  732-595-8429. Fax:  732-594-5042. E-mail:  [email protected].

     Department of Medicinal Chemistry, Merck & Co..


     Department of Metabolic Disorders, Merck & Co..

     MRL San Diego Neuroscience Center.

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    2. Nicholas A. Meanwell. Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties. ACS Medicinal Chemistry Letters 2023, 14 (4) , 350-361.
    3. Qing Tang, Alex M. Aronov, David D. Deininger, Simon Giroux, David J. Lauffer, Pan Li, Jianglin Liang, Kira McGinty, Steven Ronkin, Rebecca Swett, Nathan Waal, Diane Boucher, Pamella J. Ford, Cameron S. Moody. Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors. ACS Medicinal Chemistry Letters 2021, 12 (6) , 955-960.
    4. Gary Tresadern, Ingrid Velter, Andrés A. Trabanco, Frans Van den Keybus, Gregor J. Macdonald, Marijke V. F. Somers, Greet Vanhoof, Philip M. Leonard, Marieke B. A. C. Lamers, Yves E. M. Van Roosbroeck, Peter J. J. A. Buijnsters. [1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration. Journal of Medicinal Chemistry 2020, 63 (21) , 12887-12910.
    5. Chao-Ming Hsieh, Chun-Yi Chen, Ji-Wang Chern, Nei-Li Chan. Structure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting α-Helix Backbone Oxygen by Halogen Bonding. Journal of Medicinal Chemistry 2020, 63 (15) , 8485-8494.
    6. Xiaoqing Feng, Huanchen Wang, Mengchun Ye, Xue-Tao Xu, Ying Xu, Wenzhe Yang, Han-Ting Zhang, Guoqiang Song, Hengming Ke. Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors. Biochemistry 2018, 57 (30) , 4518-4525.
    7. Ian M. Robertson, Sandra E. Pineda-Sanabria, Ziqian Yan, Thomas Kampourakis, Yin-Biao Sun, Brian D. Sykes, and Malcolm Irving . Reversible Covalent Binding to Cardiac Troponin C by the Ca2+-Sensitizer Levosimendan. Biochemistry 2016, 55 (43) , 6032-6045.
    8. Chimed Jansen, Albert J. Kooistra, Georgi K. Kanev, Rob Leurs, Iwan J. P. de Esch, and Chris de Graaf . PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design. Journal of Medicinal Chemistry 2016, 59 (15) , 7029-7065.
    9. Zhe Li, Yinuo Wu, Ling-Jun Feng, Ruibo Wu, and Hai-Bin Luo . Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5. Journal of Chemical Theory and Computation 2014, 10 (12) , 5448-5457.
    10. Zhongming Zhang and Nikolai O. Artemyev. Determinants for Phosphodiesterase 6 Inhibition by Its γ-Subunit. Biochemistry 2010, 49 (18) , 3862-3867.
    11. Justin Kai-Chi Lau, Xiao-Bo Li and Yuen-Kit Cheng. A Substrate Selectivity and Inhibitor Design Lesson from the PDE10−cAMP Crystal Structure: A Computational Study. The Journal of Physical Chemistry B 2010, 114 (15) , 5154-5160.
    12. Zahra Mashhadi, Huimin Xu and Robert H. White. An Fe2+-Dependent Cyclic Phosphodiesterase Catalyzes the Hydrolysis of 7,8-Dihydro-d-neopterin 2′,3′-Cyclic Phosphate in Methanopterin Biosynthesis. Biochemistry 2009, 48 (40) , 9384-9392.
    13. Roya Zoraghi,, Sharron H. Francis, and, Jackie D. Corbin. Critical Amino Acids in Phosphodiesterase-5 Catalytic Site That Provide for High-Affinity Interaction with Cyclic Guanosine Monophosphate and Inhibitors. Biochemistry 2007, 46 (47) , 13554-13563.
    14. James L. Weeks, II,, Roya Zoraghi,, Sharron H. Francis, and, Jackie D. Corbin. N-Terminal Domain of Phosphodiesterase-11A4 (PDE11A4) Decreases Affinity of the Catalytic Site for Substrates and Tadalafil, and is Involved in Oligomerization. Biochemistry 2007, 46 (36) , 10353-10364.
    15. Qing Huai,, Yingjie Sun,, Huanchen Wang,, Dwight Macdonald,, Renée Aspiotis,, Howard Robinson,, Zheng Huang, and, Hengming Ke. Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase. Journal of Medicinal Chemistry 2006, 49 (6) , 1867-1873.
    16. André Iffland,, Darcy Kohls,, Simon Low,, Jing Luan,, Yan Zhang,, Michael Kothe,, Qing Cao,, Ajith V. Kamath,, Yuan-Hua Ding, and, Tom Ellenberger. Structural Determinants for Inhibitor Specificity and Selectivity in PDE2A Using the Wheat Germ in Vitro Translation System. Biochemistry 2005, 44 (23) , 8312-8325.
    17. David T. Manallack,, Richard A. Hughes, and, Philip E. Thompson. The Next Generation of Phosphodiesterase Inhibitors:  Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases. Journal of Medicinal Chemistry 2005, 48 (10) , 3449-3462.
    18. Paola Gratteri,, Claudia Bonaccini, and, Fabrizio Melani. Searching for a Reliable Orientation of Ligands in Their Binding Site:  Comparison between a Structure-Based (Glide) and a Ligand-Based (FIGO) Approach in the Case Study of PDE4 Inhibitors. Journal of Medicinal Chemistry 2005, 48 (5) , 1657-1665.
    19. Tao Liu, Anil K. Padyana, Evan T. Judd, Lei Jin, Dalia Hammoudeh, Charles Kung, Lenny Dang. Structure‐Based Design of AG‐946, a Pyruvate Kinase Activator. ChemMedChem 2024, 18
    20. Ziyu Zhu, Wentao Tang, Xuemei Qiu, Xin Xin, Jifa Zhang. Advances in targeting Phosphodiesterase 1: From mechanisms to potential therapeutics. European Journal of Medicinal Chemistry 2024, 263 , 115967.
    21. Shabnam Pourhanafi, Vildan Adar Gürsoy. Molecular Docking, Dynamics Simulation, and Physicochemical Analysis of Some Phytochemicals as Antiplatelet Agents. Letters in Drug Design & Discovery 2023, 20 (9) , 1343-1359.
    22. Yasukiyo YOSHIOKA, Yukiko IMI, Kyuichi KAWABATA, Katsumi SHIBATA, Junji TERAO, Noriyuki MIYOSHI. Theophylline Prevents Dexamethasone-Induced Atrophy in C2C12 Myotubes. Journal of Nutritional Science and Vitaminology 2023, 69 (4) , 284-291.
    23. Iryna V. Nizhenkovska, Kateryna V. Matskevych, Oksana I. Golovchenko, Oleksandr V. Golovchenko, Antonina D. Kustovska, Mikhaeel Van. New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension. Advanced Pharmaceutical Bulletin 2023, 13 (2) , 399-407.
    24. Vanha N. Pham, Christopher J. Chang. Metalloallostery and Transition Metal Signaling: Bioinorganic Copper Chemistry Beyond Active Sites. Angewandte Chemie 2023, 135 (11)
    25. Vanha N. Pham, Christopher J. Chang. Metalloallostery and Transition Metal Signaling: Bioinorganic Copper Chemistry Beyond Active Sites. Angewandte Chemie International Edition 2023, 62 (11)
    26. Maria Ercu, Michael B. Mücke, Tamara Pallien, Lajos Markó, Anastasiia Sholokh, Carolin Schächterle, Atakan Aydin, Alexa Kidd, Stephan Walter, Yasmin Esmati, Brandon J. McMurray, Daniella F. Lato, Daniele Yumi Sunaga-Franze, Philip H. Dierks, Barbara Isabel Montesinos Flores, Ryan Walker-Gray, Maolian Gong, Claudia Merticariu, Kerstin Zühlke, Michael Russwurm, Tiannan Liu, Theda U.P. Batolomaeus, Sabine Pautz, Stefanie Schelenz, Martin Taube, Hanna Napieczynska, Arnd Heuser, Jenny Eichhorst, Martin Lehmann, Duncan C. Miller, Sebastian Diecke, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Matthew A. Movsesian, Friedrich W. Herberg, Sofia K. Forslund, Dominik N. Müller, Tatiana Borodina, Philipp G. Maass, Sylvia Bähring, Norbert Hübner, Michael Bader, Enno Klussmann. Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage. Circulation 2022, 146 (23) , 1758-1778.
    27. Ilkay Erdogan Orhan, Abdur Rauf, Muhammad Saleem, Anees Ahmed Khalil. Natural Molecules as Talented Inhibitors of Nucleotide Pyrophosphatases/ Phosphodiesterases (PDEs). Current Topics in Medicinal Chemistry 2022, 22 (3) , 209-228.
    28. Colin W. Garvie, Xiaoyun Wu, Malvina Papanastasiou, Sooncheol Lee, James Fuller, Gavin R. Schnitzler, Steven W. Horner, Andrew Baker, Terry Zhang, James P. Mullahoo, Lindsay Westlake, Stephanie H. Hoyt, Marcus Toetzl, Matthew J. Ranaghan, Luc de Waal, Joseph McGaunn, Bethany Kaplan, Federica Piccioni, Xiaoping Yang, Martin Lange, Adrian Tersteegen, Donald Raymond, Timothy A. Lewis, Steven A. Carr, Andrew D. Cherniack, Christopher T. Lemke, Matthew Meyerson, Heidi Greulich. Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nature Communications 2021, 12 (1)
    29. Jie Chen, Nan Liu, Yinpin Huang, Yuanxun Wang, Yuxing Sun, Qingcui Wu, Dianrong Li, Shuanhu Gao, Hong-Wei Wang, Niu Huang, Xiangbing Qi, Xiaodong Wang. Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Nature Communications 2021, 12 (1)
    30. Arooma Maryam, Rana Rehan Khalid, Abdul Rauf Siddiqi, Abdulilah Ece. E-pharmacophore based virtual screening for identification of dual specific PDE5A and PDE3A inhibitors as potential leads against cardiovascular diseases. Journal of Biomolecular Structure and Dynamics 2021, 39 (7) , 2302-2317.
    31. Michelle Langton, Sining Sun, Chie Ueda, Max Markey, Jiahua Chen, Isaac Paddy, Paul Jiang, Natalie Chin, Amy Milne, Maria-Eirini Pandelia. The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries. Catalysts 2020, 10 (10) , 1191.
    32. Ilaria Cicalini, Barbara De Filippis, Nicola Gambacorta, Antonio Di Michele, Silvia Valentinuzzi, Alessandra Ammazzalorso, Alice Della Valle, Rosa Amoroso, Orazio Nicolotti, Piero Del Boccio, Letizia Giampietro. Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor. Molecules 2020, 25 (8) , 1817.
    33. Xiaoyun Wu, Gavin R. Schnitzler, Galen F. Gao, Brett Diamond, Andrew R. Baker, Bethany Kaplan, Kaylyn Williamson, Lindsay Westlake, Selena Lorrey, Timothy A. Lewis, Colin W. Garvie, Martin Lange, Sikander Hayat, Henrik Seidel, John Doench, Andrew D. Cherniack, Charlotte Kopitz, Matthew Meyerson, Heidi Greulich. Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12. Journal of Biological Chemistry 2020, 295 (11) , 3431-3446.
    34. Seyed Mohammad Nabavi, Sylwia Talarek, Joanna Listos, Seyed Fazel Nabavi, Kasi Pandima Devi, Marcos Roberto de Oliveira, Devesh Tewari, Sandro Argüelles, Saeed Mehrzadi, Azam Hosseinzadeh, Grazia D'onofrio, Ilkay Erdogan Orhan, Antoni Sureda, Suowen Xu, Saeedeh Momtaz, Mohammad Hosein Farzaei. Phosphodiesterase inhibitors say NO to Alzheimer's disease. Food and Chemical Toxicology 2019, 134 , 110822.
    35. Qing Liu, Andreas Herrmann, Qiang Huang. Surface Binding Energy Landscapes Affect Phosphodiesterase Isoform-Specific Inhibitor Selectivity. Computational and Structural Biotechnology Journal 2019, 17 , 101-109.
    36. Jessica Ostermeyer, Franziska Golly, Volkhard Kaever, Stefan Dove, Roland Seifert, Erich H. Schneider. cUMP hydrolysis by PDE3B. Naunyn-Schmiedeberg's Archives of Pharmacology 2018, 391 (9) , 891-905.
    37. Takakazu Mitani, Tomohide Takaya, Naoki Harada, Shigeru Katayama, Ryoichi Yamaji, Soichiro Nakamura, Hitoshi Ashida. Theophylline suppresses interleukin-6 expression by inhibiting glucocorticoid receptor signaling in pre-adipocytes. Archives of Biochemistry and Biophysics 2018, 646 , 98-106.
    38. Camila Muñoz-Gutiérrez, Daniela Cáceres-Rojas, Francisco Adasme-Carreño, Iván Palomo, Eduardo Fuentes, Julio Caballero, . Docking and quantitative structure–activity relationship of bi-cyclic heteroaromatic pyridazinone and pyrazolone derivatives as phosphodiesterase 3A (PDE3A) inhibitors. PLOS ONE 2017, 12 (12) , e0189213.
    39. Stefan Kunz, Vreni Balmer, Geert Jan Sterk, Michael P. Pollastri, Rob Leurs, Norbert Müller, Andrew Hemphill, Cornelia Spycher, . The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target. PLOS Neglected Tropical Diseases 2017, 11 (9) , e0005891.
    40. Lakshmi Krishnamoorthy, Joseph A Cotruvo, Jefferson Chan, Harini Kaluarachchi, Abigael Muchenditsi, Venkata S Pendyala, Shang Jia, Allegra T Aron, Cheri M Ackerman, Mark N Vander Wal, Timothy Guan, Lukas P Smaga, Samouil L Farhi, Elizabeth J New, Svetlana Lutsenko, Christopher J Chang. Copper regulates cyclic-AMP-dependent lipolysis. Nature Chemical Biology 2016, 12 (8) , 586-592.
    41. João Monteiro, Marco Alves, Pedro Oliveira, Branca Silva. Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules 2016, 21 (8) , 974.
    42. Bagher Alinejad, Reza Shafiee-Nick, Ahmad Ghorbani, Hamid Sadeghian. MC2, a new phosphodiesterase-3 inhibitor with antilipolytic and hypolipidemic effects in normal and diabetic rats. International Journal of Diabetes in Developing Countries 2015, 35 (4) , 408-417.
    43. Christos Kontogiorgis, Orazio Nicolotti, Giuseppe Felice Mangiatordi, Massimiliano Tognolini, Foteini Karalaki, Carmine Giorgio, Alexandros Patsilinakos, Angelo Carotti, Dimitra Hadjipavlou-Litina, Elisabetta Barocelli. Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry 2015, 30 (6) , 925-933.
    44. Eleonora Corradini, Gruson Klaasse, Ulrike Leurs, Albert J. R. Heck, Nathaniel I. Martin, Arjen Scholten. Charting the interactome of PDE3A in human cells using an IBMX based chemical proteomics approach. Molecular BioSystems 2015, 11 (10) , 2786-2797.
    45. Marco Conti, Wito Richter. Phosphodiesterases and Cyclic Nucleotide Signaling In The CNS. 2014, 1-46.
    46. Frank S. Menniti, Niels Plath, Niels Svenstrup, Christopher J. Schmidt. Pharmacological Manipulation of Cyclic Nucleotide Phosphodiesterase Signaling for The Treatment of Neurological and Psychiatric Disorders In The Brain. 2014, 77-114.
    47. Hengming Ke, Huanchen Wang, Mengchun Ye, Yingchun Huang. Crystal Structures of Phosphodiesterases and Implication on Discovery of Inhibitors. 2014, 145-170.
    48. Jayvardhan Pandit. PDE4: New Structural Insights into the Regulatory Mechanism and Implications for the Design of Selective Inhibitors. 2014, 29-44.
    49. Mario Di Braccio, Giancarlo Grossi, Maria Grazia Signorello, Giuliana Leoncini, Elena Cichero, Paola Fossa, Silvana Alfei, Gianluca Damonte. Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2- a ]benzimidazol-4(10 H )-ones. European Journal of Medicinal Chemistry 2013, 62 , 564-578.
    50. Koji Ochiai, Satoshi Takita, Akihiko Kojima, Tomohiko Eiraku, Kazuhiko Iwase, Tetsuya Kishi, Akira Ohinata, Yuichi Yageta, Tokutaro Yasue, David R. Adams, Yasushi Kohno. Phosphodiesterase inhibitors. Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Bioorganic & Medicinal Chemistry Letters 2013, 23 (1) , 375-381.
    51. Ashraf Hassan Abadi, Marwa Saeed Hany, Shimaa Awadain Elsharif, Amal Abdel Haleem Eissa, Bernard DeWayne Gary, Heather Nicole Tinsley, Gary Anthony Piazza. Modulating the Cyclic Guanosine Monophosphate Substrate Selectivity of the Phosphodiesterase 3 Inhibitors by Pyridine, Pyrido[2,3-d]pyrimidine Derivatives and Their Effects upon the Growth of HT-29 Cancer Cell Line. Chemical and Pharmaceutical Bulletin 2013, 61 (4) , 405-410.
    52. Daniella Ramos Martins, Francine Pazini, Vinícius de Medeiros Alves, Soraya Santana de Moura, Luciano Morais Lião, Mariana Torquato Quezado de Magalhães, Marize Campos Valadares, Carolina Horta Andrade, Ricardo Menegatti, Matheus Lavorenti Rocha. Synthesis, Docking Studies, Pharmacological Activity and Toxicity of a Novel Pyrazole Derivative (LQFM 021)—Possible Effects on Phosphodiesterase. Chemical and Pharmaceutical Bulletin 2013, 61 (5) , 524-531.
    53. Justin Kai‐Chi Lau, Yuen‐Kit Cheng. An update view on the substrate recognition mechanism of phosphodiesterases: A computational study of PDE10 and PDE4 bound with cyclic nucleotides. Biopolymers 2012, 97 (11) , 910-922.
    54. Koji Ochiai, Satoshi Takita, Akihiko Kojima, Tomohiko Eiraku, Naoki Ando, Kazuhiko Iwase, Tetsuya Kishi, Akira Ohinata, Yuichi Yageta, Tokutaro Yasue, David R. Adams, Yasushi Kohno. Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones. Bioorganic & Medicinal Chemistry Letters 2012, 22 (18) , 5833-5838.
    55. Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Kazunori Fukuchi, Tokutaro Yasue, David R. Adams, Robert W. Allcock, Zhong Jiang, Yasushi Kohno. Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure–activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity. Bioorganic & Medicinal Chemistry 2012, 20 (5) , 1644-1658.
    56. Sung-Jun Park, Faiyaz Ahmad, Andrew Philp, Keith Baar, Tishan Williams, Haibin Luo, Hengming Ke, Holger Rehmann, Ronald Taussig, Alexandra L. Brown, Myung K. Kim, Michael A. Beaven, Alex B. Burgin, Vincent Manganiello, Jay H. Chung. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases. Cell 2012, 148 (3) , 421-433.
    57. Hilla Ovadia, Yulia Haim, Ori Nov, Orna Almog, Julia Kovsan, Nava Bashan, Moran Benhar, Assaf Rudich. Increased Adipocyte S-Nitrosylation Targets Anti-lipolytic Action of Insulin. Journal of Biological Chemistry 2011, 286 (35) , 30433-30443.
    58. Thomas Seebeck, Geert Jan Sterk, Hengming Ke. Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite. Future Medicinal Chemistry 2011, 3 (10) , 1289-1306.
    59. Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. Adams. Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast. Bioorganic & Medicinal Chemistry Letters 2011, 21 (11) , 3307-3312.
    60. Alexander V. Stepakov, Michail A. Kinzhalov, Vitaly M. Boitsov, Liubov V. Stepakova, Galina L. Starova, Sergey Yu. Vyazmin, Elena V. Grinenko. A new approach to the synthesis of 4-(N-aryl)carbamoylmethyl-4,5-dihydropyridazin-3(2H)-ones. Tetrahedron Letters 2011, 52 (24) , 3146-3149.
    61. Sharron H. Francis, Mitsi A. Blount, Jackie D. Corbin. Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions. Physiological Reviews 2011, 91 (2) , 651-690.
    62. Ki Young Kim, Hyuk Lee, Sung-Eun Yoo, Seong Hwan Kim, Nam Sook Kang. Discovery of new inhibitor for PDE3 by virtual screening. Bioorganic & Medicinal Chemistry Letters 2011, 21 (6) , 1617-1620.
    63. Sharron H. Francis, Konjeti R. Sekhar, Hengming Ke, Jackie D. Corbin. Inhibition of Cyclic Nucleotide Phosphodiesterases by Methylxanthines and Related Compounds. 2011, 93-133.
    64. Sharron H. Francis, Miles D. Houslay, Marco Conti. Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action. 2011, 47-84.
    65. Hengming Ke, Huanchen Wang, Mengchun Ye. Structural Insight into the Substrate Specificity of Phosphodiesterases. 2011, 121-134.
    66. Roderick E. Hubbard. Structure-based drug discovery and protein targets in the CNS. Neuropharmacology 2011, 60 (1) , 7-23.
    67. Tiziana Pietrangelo, Letizia Giampietro, Barbara De Filippis, Rita La Rovere, Stefania Fulle, Rosa Amoroso. Effect of milrinone analogues on intracellular calcium increase in single living H9C2 cardiac cells. European Journal of Medicinal Chemistry 2010, 45 (11) , 4928-4933.
    68. Kelly R. Bales, Niels Plath, Niels Svenstrup, Frank S. Menniti. Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer’s Disease. 2010, 57-90.
    69. Mohsen Nikpour, Hamid Sadeghian, Mohammad Reza Saberi, Reza Shafiee Nick, Seyed Mohammad Seyedi, Azar Hosseini, Heydar Parsaee, Alireza Taghian Dasht Bozorg. Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors. Bioorganic & Medicinal Chemistry 2010, 18 (2) , 855-862.
    70. Jayvardhan Pandit, Michael D. Forman, Kimberly F. Fennell, Keith S. Dillman, Frank S. Menniti. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proceedings of the National Academy of Sciences 2009, 106 (43) , 18225-18230.
    71. Hamid Sadeghian, Seyed Mohammad Seyedi, Mohammad Reza Saberi, Reza Shafiee Nick, Azar Hosseini, Mehdi Bakavoli, Seyed Mohammad Taghi Mansouri, Heydar Parsaee. Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents. Journal of Enzyme Inhibition and Medicinal Chemistry 2009, 24 (4) , 918-929.
    72. Jeremy M. Murray, Dirksen E. Bussiere. Targeting the Purinome. 2009, 47-92.
    73. Sharron H. Francis, Jackie D. Corbin, Erwin Bischoff. Cyclic GMP-Hydrolyzing Phosphodiesterases. 2009, 367-408.
    74. Shenping Liu, Mahmoud N. Mansour, Keith S. Dillman, Jose R. Perez, Dennis E. Danley, Paul A. Aeed, Samuel P. Simons, Peter K. LeMotte, Frank S. Menniti. Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proceedings of the National Academy of Sciences 2008, 105 (36) , 13309-13314.
    75. Tasmina A. Goraya, Nanako Masada, Antonio Ciruela, Debbie Willoughby, Michael A. Clynes, Dermot M.F. Cooper. Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+. Cellular Signalling 2008, 20 (2) , 359-374.
    76. George G. Holz, Oleg G. Chepurny, Frank Schwede. Epac-selective cAMP analogs: New tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors. Cellular Signalling 2008, 20 (1) , 10-20.
    77. E. A. Salter, Kerrie A. O'Brien, R. Wesley Edmunds, A. Wierzbicki. ONIOM investigation of nucleotide selectivity in phosphodiesterases 3 and 4. International Journal of Quantum Chemistry 2008, 108 (6) , 1189-1199.
    78. Huanchen Wang, Zier Yan, Jie Geng, Stefan Kunz, Thomas Seebeck, Hengming Ke. Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite‐selective inhibitors. Molecular Microbiology 2007, 66 (4) , 1029-1038.
    79. Francesca Spyrakis, Alessio Amadasi, Micaela Fornabaio, Donald J. Abraham, Andrea Mozzarelli, Glen E. Kellogg, Pietro Cozzini. The consequences of scoring docked ligand conformations using free energy correlations. European Journal of Medicinal Chemistry 2007, 42 (7) , 921-933.
    80. Marco Conti, Joseph Beavo. Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling. Annual Review of Biochemistry 2007, 76 (1) , 481-511.
    81. Z. Huang, R. Dias, T. Jones, S. Liu, A. Styhler, D. Claveau, F. Otu, K. Ng, F. Laliberte, L. Zhang, P. Goetghebeur, W.M. Abraham, D. Macdonald, D. Dubé, M. Gallant, P. Lacombe, Y. Girard, R.N. Young, M.J. Turner, D.W. Nicholson, J.A. Mancini. L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochemical Pharmacology 2007, 73 (12) , 1971-1981.
    82. Wei Yuan, Andrés López Bernal. Cyclic AMP signalling pathways in the regulation of uterine relaxation. BMC Pregnancy and Childbirth 2007, 7 (S1)
    83. Huanchen Wang, Yudong Liu, Jing Hou, Meiyan Zheng, Howard Robinson, Hengming Ke. Structural insight into substrate specificity of phosphodiesterase 10. Proceedings of the National Academy of Sciences 2007, 104 (14) , 5782-5787.
    84. D.P. Rotella. Phosphodiesterases. 2007, 919-957.
    85. Joseph A. Beavo. Phosphodiesterase 3B. 2007, 1-8.
    86. Huanchen Wang, Hengming Ke. Structure, Catalytic Mechanism, and Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases. 2006
    87. Eva Degerman, Vincent Manganiello. Phosphodiesterase 3B. 2006
    88. Kam Zhang. Crystal Structure of Phosphodiesterase Families and the Potential for Rational Drug Design. 2006
    89. Su-Hwi Hung, Wei Zhang, Robin A. Pixley, Bradford A. Jameson, Yu Chu Huang, Roberta F. Colman, Robert W. Colman. New Insights from the Structure-Function Analysis of the Catalytic Region of Human Platelet Phosphodiesterase 3A. Journal of Biological Chemistry 2006, 281 (39) , 29236-29244.
    90. Andrew T. Bender, Joseph A. Beavo. Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use. Pharmacological Reviews 2006, 58 (3) , 488-520.
    91. Huanchen Wang, Yudong Liu, Qing Huai, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Jackie D. Corbin, Howard Robinson, Zhongcheng Xin, Guiting Lin, Hengming Ke. Multiple Conformations of Phosphodiesterase-5. Journal of Biological Chemistry 2006, 281 (30) , 21469-21479.
    92. Zheng Huang, Susana Liu, Lei Zhang, Myriam Salem, Gillian M. Greig, Chi Chung Chan, Yutaka Natsumeda, Kazuhito Noguchi. Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sciences 2006, 78 (23) , 2663-2668.
    93. N. S. Kang, C. H. Chae, S.-E. Yoo. Study on the hydrolysis mechanism of phosphodiesterase 4 using molecular dynamics simulations. Molecular Simulation 2006, 32 (5) , 369-374.
    94. Claire Lugnier. Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacology & Therapeutics 2006, 109 (3) , 366-398.
    95. Roya Zoraghi, Jackie D. Corbin, Sharron H. Francis. Phosphodiesterase-5 Gln817 Is Critical for cGMP, Vardenafil, or Sildenafil Affinity. Journal of Biological Chemistry 2006, 281 (9) , 5553-5558.
    96. Mercedes Pozuelo Rubio, David G. Campbell, Nicholas A. Morrice, Carol Mackintosh. Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428. Biochemical Journal 2005, 392 (1) , 163-172.
    97. Francesco V. Rao, Ole A. Andersen, Kalpit A. Vora, Julie A. DeMartino, Daan M.F. van Aalten. Methylxanthine Drugs Are Chitinase Inhibitors: Investigation of Inhibition and Binding Modes. Chemistry & Biology 2005, 12 (9) , 973-980.
    98. Huanchen Wang, Yudong Liu, Yuxiang Chen, Howard Robinson, Hengming Ke. Multiple Elements Jointly Determine Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases 4 and 7. Journal of Biological Chemistry 2005, 280 (35) , 30949-30955.
    99. Graeme L. Card, Bruce P. England, Yoshihisa Suzuki, Daniel Fong, Ben Powell, Byunghun Lee, Catherine Luu, Maryam Tabrizizad, Sam Gillette, Prabha N. Ibrahim, Dean R. Artis, Gideon Bollag, Michael V. Milburn, Sung-Hou Kim, Joseph Schlessinger, Kam Y.J. Zhang. Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases. Structure 2004, 12 (12) , 2233-2247.

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