5u7i

From Proteopedia

Jump to: navigation, search

PDE2 catalytic domain complexed with inhibitors

Structural highlights

5u7i is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:7XS, MG, ZN
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

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.,Helal CJ, Arnold EP, Boyden TL, Chang C, Chappie TA, Fennell KF, Forman MD, Hajos M, Harms JF, Hoffman WE, Humphrey JM, Kang Z, Kleiman RJ, Kormos BL, Lee CW, Lu J, Maklad N, McDowell L, Mente S, O'Connor RE, Pandit J, Piotrowski M, Schmidt AW, Schmidt CJ, Ueno H, Verhoest PR, Yang EX J Med Chem. 2017 Jul 13;60(13):5673-5698. doi: 10.1021/acs.jmedchem.7b00397. Epub, 2017 Jun 16. PMID:28574706[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Loading citation details..
Citations
0 reviews cite this structure
Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189.
Stepan et al. (2018)
-1 more
5 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Helal CJ, Arnold EP, Boyden TL, Chang C, Chappie TA, Fennell KF, Forman MD, Hajos M, Harms JF, Hoffman WE, Humphrey JM, Kang Z, Kleiman RJ, Kormos BL, Lee CW, Lu J, Maklad N, McDowell L, Mente S, O'Connor RE, Pandit J, Piotrowski M, Schmidt AW, Schmidt CJ, Ueno H, Verhoest PR, Yang EX. Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor. J Med Chem. 2017 Jul 13;60(13):5673-5698. doi: 10.1021/acs.jmedchem.7b00397. Epub, 2017 Jun 16. PMID:28574706 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00397

Contents


PDB ID 5u7i

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/5u7i"
Personal tools