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Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases
Open accessAbstract
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.
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Robichaud, A., Stamatiou, P. B., Jin, S.-L. C., Lachance, N., MacDonald, D., Laliberté, F., Liu, S., Huang, Z., Conti, M., & Chan, C.-C. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15506 · Cited by 267
PHARMACOLOGY OF PHOSPHODIESTERASE‐5 INHIBITORS
Corbin, J., & Francis, S. (2002) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2002.tb11296.x · Cited by 260
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Burgin, A. B., Magnusson, O. T., Singh, J., Witte, P., Staker, B. L., Bjornsson, J. M., Thorsteinsdottir, M., Hrafnsdottir, S., Hagen, T., Kiselyov, A. S., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1598 · Cited by 397
Phosphodiesterases in the CNS: targets for drug development
Menniti, F. S., Faraci, W. S., & Schmidt, C. J. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2058 · Cited by 391
PDE4 inhibitors: current status
Spina, D. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.307 · Cited by 340
Sharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331
Metadata
- Authors
- Card, G. L., England, B. P., Suzuki, Y., Fong, D., Powell, B., Lee, B., Luu, C., Tabrizizad, M., Gillette, S., Ibrahim, P. N., Artis, D. R., Bollag, G., Milburn, M. V., Kim, S.-H., Schlessinger, J., & Zhang, K. Y. J.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 12
- Issue
- 12
- Pages
- 2233-2247
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2119774957
- Cited by
- 432
- References
- 2
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Card, G. L., England, B. P., Suzuki, Y., Fong, D., Powell, B., Lee, B., Luu, C., Tabrizizad, M., Gillette, S., Ibrahim, P. N., Artis, D. R., Bollag, G., Milburn, M. V., Kim, S.-H., Schlessinger, J., & Zhang, K. Y. J. (2004). Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases. Structure. https://doi.org/10.1016/j.str.2004.10.004
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