The rational design of inhibitors of nitric oxide formation by inducible nitric oxide synthase.
A series of compounds was rationally designed as inhibitors of dimer formation of the inducible isoform of nitric oxide synthase, and subsequent nitric oxide production. The conformation of two fragments obtained from a crystal structure was utilized to design a tether connecting those same two fragments. The resulting compounds were potent dimerization inhibitors that bound to the enzyme in a similar conformation as the fragments.
Whitlow
Marc
M
Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA.
Adler
Marc
M
Davey
David
D
Huang
Qinglan
Q
Koovakkat
Sunil
S
Parkinson
John F
JF
Pham
Eric
E
Polokoff
Mark
M
Xu
Wei
W
Yuan
Shendong
S
Phillips
Gary
G
D001665:Binding Sites; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D052247:Nitric Oxide Synthase Type II