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PDBsum entry 4zth
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PDB id:
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Transferase
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Title:
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Structure of human p38amapk-arylpyridazinylpyridine fragment complex used in inhibitor discovery
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Structure:
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Mitogen-activated protein kinase 14. Chain: a. Synonym: mapk 14,cytokine suppressive anti-inflammatory drug-binding protein,csbp,map kinase mxi2,max-interacting protein 2,mitogen- activated protein kinase p38 alpha,map kinase p38 alpha,stress- activated protein kinase 2a,sapk2a. Engineered: yes. Other_details: human p38 alpha map kinase
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2, sapk2a. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.15Å
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R-factor:
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0.184
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R-free:
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0.240
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Authors:
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V.L.Grum-Tokars,S.M.Roy,D.M.Watterson
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Key ref:
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S.M.Roy
et al.
(2019).
A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction.
J Med Chem,
62,
5298-5311.
PubMed id:
DOI:
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Date:
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14-May-15
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Release date:
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22-Jun-16
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PROCHECK
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Headers
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References
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Q16539
(MK14_HUMAN) -
Mitogen-activated protein kinase 14 from Homo sapiens
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Seq:
Struc:
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360 a.a.
339 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.24
- mitogen-activated protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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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
62:5298-5311
(2019)
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PubMed id:
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A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction.
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S.M.Roy,
G.Minasov,
O.Arancio,
L.W.Chico,
L.J.Van Eldik,
W.F.Anderson,
J.C.Pelletier,
D.M.Watterson.
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ABSTRACT
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The p38αMAPK is a serine/threonine protein kinase and a key node in the
intracellular signaling networks that transduce and amplify stress signals into
physiological changes. A preponderance of preclinical data and clinical
observations established p38αMAPK as a brain drug discovery target involved in
neuroinflammatory responses and synaptic dysfunction in multiple degenerative
and neuropsychiatric brain disorders. We summarize the discovery of highly
selective, brain-penetrant, small molecule p38αMAPK inhibitors that are
efficacious in diverse animal models of neurologic disorders. A crystallography
and pharmacoinformatic approach to fragment expansion enabled the discovery of
an efficacious hit. The addition of secondary pharmacology screens to refinement
delivered lead compounds with improved selectivity, appropriate
pharmacodynamics, and efficacy. Safety considerations and additional secondary
pharmacology screens drove optimization that delivered the drug candidate
MW01-18-150SRM (MW150), currently in early stage clinical trials.
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Links
