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PDBsum entry 6imr
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Hydrolase/hydrolase inhibitor
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PDB id
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6imr
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of pde4d complexed with a novel inhibitor
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Structure:
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Camp-specific 3',5'-cyclic phosphodiesterase 4d. Chain: a, b. Synonym: pde4d, dpde3,pde43. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4d, dpde3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.50Å
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R-factor:
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0.212
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R-free:
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0.237
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Authors:
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X.L.Zhang,H.X.Su,Y.C.Xu
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Key ref:
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X.Zhang
et al.
(2019).
Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
J Med Chem,
62,
5579-5593.
PubMed id:
DOI:
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Date:
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23-Oct-18
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Release date:
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23-Oct-19
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PROCHECK
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Headers
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References
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Q08499
(PDE4D_HUMAN) -
3',5'-cyclic-AMP phosphodiesterase 4D from Homo sapiens
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Seq:
Struc:
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809 a.a.
325 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.3.1.4.53
- 3',5'-cyclic-AMP phosphodiesterase.
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Reaction:
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3',5'-cyclic AMP + H2O = AMP + H+
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3',5'-cyclic AMP
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+
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H2O
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=
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AMP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
62:5579-5593
(2019)
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PubMed id:
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Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
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X.Zhang,
G.Dong,
H.Li,
W.Chen,
J.Li,
C.Feng,
Z.Gu,
F.Zhu,
R.Zhang,
M.Li,
W.Tang,
H.Liu,
Y.Xu.
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ABSTRACT
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Psoriasis is a common, chronic inflammatory disease characterized by abnormal
skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to
lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4
inhibitor acting as an effective, safe, and convenient therapeutic agent, we
constructed a library consisting of berberine analogues, and compound 2 with a
tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The
structure-aided and cell-based structure-activity relationship studies on a
series of tetrahydro-isoquinolines lead to efficient discovery of a qualified
lead compound (16) with the high potency and selectivity, well-characterized
binding mechanism, high cell permeability, good safety and pharmacokinetic
profile, and impressive in vivo efficacy on antipsoriasis, in particular with a
topical application. Thus, our study presents a prime example for efficient
discovery of novel, potent lead compounds derived from natural products using a
combination of medicinal chemistry, biochemical, biophysical, and
pharmacological approaches.
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