title: Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.
abstract: 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.
authors.affiliation: Telik, Inc., 3165 Porter Drive, Palo Alto, California 94304, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hsu
authors.forename: Danying
authors.initials: D
authors.lastname: Cai
authors.forename: Komath
authors.initials: K
authors.lastname: Damodaran
authors.forename: Reinaldo F
authors.initials: RF
authors.lastname: Gomez
authors.forename: James G
authors.initials: JG
authors.lastname: Keck
authors.forename: Edgardo
authors.initials: E
authors.lastname: Laborde
authors.forename: Robert T
authors.initials: RT
authors.lastname: Lum
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Macke
authors.forename: Graeme
authors.initials: G
authors.lastname: Martin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schow
authors.forename: Reyna J
authors.initials: RJ
authors.lastname: Simon
authors.forename: Hugo O
authors.initials: HO
authors.lastname: Villar
authors.forename: Michael M
authors.initials: MM
authors.lastname: Wick
authors.forename: Paul
authors.initials: P
authors.lastname: Beroza
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen