| Structural highlights
5tzh is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 5tz3, 5tza, 5tzc, 5tzw, 5tzx, 5tzz, 5u00 |
| Activity: | 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2]
Publication Abstract from PubMed
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.
Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.,Gomez L, Massari ME, Vickers T, Freestone G, Vernier W, Ly K, Xu R, McCarrick M, Marrone T, Metz M, Yan YG, Yoder ZW, Lemus R, Broadbent NJ, Barido R, Warren N, Schmelzer K, Neul D, Lee D, Andersen CB, Sebring K, Aertgeerts K, Zhou X, Tabatabaei A, Peters M, Breitenbucher JG J Med Chem. 2017 Feb 21. doi: 10.1021/acs.jmedchem.6b01793. PMID:28165743[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
- ↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
- ↑ Gomez L, Massari ME, Vickers T, Freestone G, Vernier W, Ly K, Xu R, McCarrick M, Marrone T, Metz M, Yan YG, Yoder ZW, Lemus R, Broadbent NJ, Barido R, Warren N, Schmelzer K, Neul D, Lee D, Andersen CB, Sebring K, Aertgeerts K, Zhou X, Tabatabaei A, Peters M, Breitenbucher JG. Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders. J Med Chem. 2017 Feb 21. doi: 10.1021/acs.jmedchem.6b01793. PMID:28165743 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01793
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