Docking study yields four novel inhibitors of the protooncogene Pim-1 kinase.
To supplement the hits from a high throughput screen, docking was performed against Pim-1 kinase. Glide docking was augmented with a filter to require traditional or aromatic CH..O hydrogen bonds to the kinase hinge. Four diverse actives, of 96 molecules assayed, had K(i) values between 0.091 and 4.5 microM. This gives a 14-fold enrichment over the earlier HTS run, and the two crystal structures solved confirmed the binding modes predicted by docking.
Pierce
Albert C
AC
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA. al_pierce@vrtx.com
Jacobs
Marc
M
Stuver-Moody
Cameron
C
D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008024:Ligands; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1