4d08

PDE2a catalytic domain in complex with a brain penetrant inhibitorPDE2a catalytic domain in complex with a brain penetrant inhibitor

Structural highlights

4d08 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.
Ligands:	, ,
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

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 muM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.,Buijnsters P, De Angelis M, Langlois X, Rombouts FJ, Sanderson W, Tresadern G, Ritchie A, Trabanco AA, VanHoof G, Roosbroeck YV, Andres JI ACS Med Chem Lett. 2014 Jul 22;5(9):1049-53. doi: 10.1021/ml500262u. eCollection , 2014 Sep 11. PMID:25221665^[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
↑ Buijnsters P, De Angelis M, Langlois X, Rombouts FJ, Sanderson W, Tresadern G, Ritchie A, Trabanco AA, VanHoof G, Roosbroeck YV, Andres JI. Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement. ACS Med Chem Lett. 2014 Jul 22;5(9):1049-53. doi: 10.1021/ml500262u. eCollection , 2014 Sep 11. PMID:25221665 doi:http://dx.doi.org/10.1021/ml500262u

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OCA

[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] Buijnsters P, De Angelis M, Langlois X, Rombouts FJ, Sanderson W, Tresadern G, Ritchie A, Trabanco AA, VanHoof G, Roosbroeck YV, Andres JI. Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement. ACS Med Chem Lett. 2014 Jul 22;5(9):1049-53. doi: 10.1021/ml500262u. eCollection , 2014 Sep 11. PMID:25221665 doi:http://dx.doi.org/10.1021/ml500262u

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4d08

PDE2a catalytic domain in complex with a brain penetrant inhibitorPDE2a catalytic domain in complex with a brain penetrant inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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4d08

PDE2a catalytic domain in complex with a brain penetrant inhibitorPDE2a catalytic domain in complex with a brain penetrant inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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