PMID- 25001371
OWN - NLM
STAT- MEDLINE
DCOM- 20150901
LR  - 20211021
IS  - 1573-4935 (Electronic)
IS  - 0144-8463 (Print)
IS  - 0144-8463 (Linking)
VI  - 34
IP  - 4
DP  - 2014 Aug 11
TI  - Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open 
      conformation.
LID - 10.1042/BSR20140071 [doi]
LID - e00133
AB  - The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic 
      plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly 
      reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR 
      hypofunction is thought to be a foundational defect in schizophrenia, hDAAO 
      inhibitors have potential as treatments for schizophrenia and other nervous 
      system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO 
      activity. We used computational tools to design a focused, purchasable library of 
      compounds. After screening this library for hDAAO inhibition, we identified the 
      structurally novel compound, 'compound 2' 
      [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low 
      nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to 
      enrich for compounds that were competitive for both D-serine and FAD, compound 2 
      actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as 
      benzoic acid. Compound 2 and an analog were independently co-crystalized with 
      hDAAO. These compounds stabilized a novel conformation of hDAAO in which the 
      active-site lid was in an open position. These results confirm previous 
      hypotheses regarding active-site lid flexibility of mammalian D-amino acid 
      oxidases and could assist in the design of the next generation of hDAAO 
      inhibitors.
FAU - Terry-Lorenzo, Ryan T
AU  - Terry-Lorenzo RT
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Chun, Lawrence E
AU  - Chun LE
AD  - daggerEmerald Bio, Bainbridge Island, WA 98110, U.S.A.
FAU - Brown, Scott P
AU  - Brown SP
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Heffernan, Michele L R
AU  - Heffernan ML
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Fang, Q Kevin
AU  - Fang QK
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Orsini, Michael A
AU  - Orsini MA
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Pollegioni, Loredano
AU  - Pollegioni L
FAU - Hardy, Larry W
AU  - Hardy LW
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Spear, Kerry L
AU  - Spear KL
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
FAU - Large, Thomas H
AU  - Large TH
AD  - *Discovery Research Department, Sunovion Pharmaceuticals, Marlborough, MA 01752, 
      U.S.A.
LA  - eng
PT  - Journal Article
DEP - 20140811
PL  - England
TA  - Biosci Rep
JT  - Bioscience reports
JID - 8102797
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 452VLY9402 (Serine)
RN  - EC 1.4.3.3 (D-Amino-Acid Oxidase)
SB  - IM
MH  - Carrier Proteins/metabolism
MH  - Catalytic Domain/*drug effects
MH  - D-Amino-Acid Oxidase/*antagonists & inhibitors
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Schizophrenia/metabolism
MH  - Serine/metabolism
PMC - PMC4127593
EDAT- 2014/07/09 06:00
MHDA- 2015/09/02 06:00
PMCR- 2014/08/11
CRDT- 2014/07/09 06:00
PHST- 2014/07/09 06:00 [entrez]
PHST- 2014/07/09 06:00 [pubmed]
PHST- 2015/09/02 06:00 [medline]
PHST- 2014/08/11 00:00 [pmc-release]
AID - BSR20140071 [pii]
AID - e00133 [pii]
AID - 10.1042/BSR20140071 [doi]
PST - epublish
SO  - Biosci Rep. 2014 Aug 11;34(4):e00133. doi: 10.1042/BSR20140071.