Structure-based virtual screening for low molecular weight chemical starting points for dipeptidyl peptidase IV inhibitors.
Structure-based virtual screening was performed against the target dipeptidyl peptidase IV (DPP-IV) to identify good chemical starting points for medicinal chemistry. A database of available compounds was filtered by calculated physical properties and undesired chemistry. This database was matched against two in-house designed DPP-IV pharmacophores, and the hits from these pharmacophore searches were docked into a DPP-IV crystal structure. Compounds were then selected for testing and 51 active compounds were identified from a list of 4000 compounds tested. These had activities ranging from 30% to 82% when tested at a concentration of 30 microM in an enzyme inhibition assay.
Ward
Richard A
RA
Cancer Discovery, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. richard.a.ward@astrazeneca.com
Perkins
Tim D J
TD
Stafford
Jackie
J
D000465:Algorithms; D001665:Binding Sites; D016208:Databases, Factual; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D008024:Ligands; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4