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PDBsum entry 4gh6
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Hydrolase/hydrolase inhibitor
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PDB id
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4gh6
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References listed in PDB file
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Key reference
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Title
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Structure-Based discovery of highly selective phosphodiesterase-9a inhibitors and implications for inhibitor design.
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Authors
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F.Meng,
J.Hou,
Y.X.Shao,
P.Y.Wu,
M.Huang,
X.Zhu,
Y.Cai,
Z.Li,
J.Xu,
P.Liu,
H.B.Luo,
Y.Wan,
H.Ke.
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Ref.
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J Med Chem, 2012,
55,
8549-8558.
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PubMed id
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Abstract
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A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of
6-amino-pyrazolopyrimidinone have been discovered by a combination of
structure-based design and computational docking. This procedure significantly
saved the load of chemical synthesis and is an effective method for the
discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3
μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of
selectivity against other PDE families. The crystal structure of the PDE9
catalytic domain in complex with 28 has been determined and shows a hydrogen
bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold
selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of
BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and
PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.
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