Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.
We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.
Hsu
Nancy
N
Telik, Inc., 3165 Porter Drive, Palo Alto, California 94304, USA.
Cai
Danying
D
Damodaran
Komath
K
Gomez
Reinaldo F
RF
Keck
James G
JG
Laborde
Edgardo
E
Lum
Robert T
RT
Macke
Thomas J
TJ
Martin
Graeme
G
Schow
Steven R
SR
Simon
Reyna J
RJ
Villar
Hugo O
HO
Wick
Michael M
MM
Beroza
Paul
P
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008962:Models, Theoretical; D015394:Molecular Structure; D011446:Prospective Studies; D011451:Prostaglandin-Endoperoxide Synthases; D021281:Quantitative Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen