A fragment-based approach to identifying S-adenosyl-l-methionine -competitive inhibitors of catechol O-methyl transferase (COMT).
Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.
Medicinal Chemistry, ‡Structural Biology, §Discovery Biology, ∥Analytical Chemistry, Takeda California Inc. , 10410 Science Center Drive San Diego California 92121, United States.
Marion
M
Lanier
Geza
G
Ambrus
Derek C
DC
Cole
Richard
R
Davenport
Jonathan
J
Ellery
Richard
R
Fosbeary
Andy J
AJ
Jennings
Akito
A
Kadotani
Yusuke
Y
Kamada
Ruhi
R
Kamran
Shin-Ichi
S
Matsumoto
Atsushi
A
Mizukami
Shoichi
S
Okubo
Kengo
K
Okada
Kumar
K
Saikatendu
Louise
L
Walsh
Haihong
H
Wu
Mark S
MS
Hixon
D000818:Animals; D001665:Binding Sites; D002394:Catechol O-Methyltransferase / Q000737:chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
D065098:Catechol O-Methyltransferase Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D014230:Triazoles; D012436:S-Adenosylmethionine; D002394:Catechol O-Methyltransferase