6B96

Crystal Structure of PDE2 in complex with compound 16

Summary for 6B96

• Entry DOI: 10.2210/pdb6b96/pdb
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase 2, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• Total number of polymer chains: 2
• Total formula weight: 88400.62

Authors

Lu, J. (deposition date: 2017-10-10, release date: 2017-11-22, Last modification date: 2024-03-06)

Primary citation

Forster, A.B.,Abeywickrema, P.,Bunda, J.,Cox, C.D.,Cabalu, T.D.,Egbertson, M.,Fay, J.,Getty, K.,Hall, D.,Kornienko, M.,Lu, J.,Parthasarathy, G.,Reid, J.,Sharma, S.,Shipe, W.D.,Smith, S.M.,Soisson, S.,Stachel, S.J.,Su, H.P.,Wang, D.,Berger, R.
The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design.
Bioorg. Med. Chem. Lett., 27:5167-5171, 2017

PubMed Abstract: We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (K = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.

PubMed: 29113762
DOI: 10.1016/j.bmcl.2017.10.054

Experimental method

X-RAY DIFFRACTION (1.88 Å)