CONFIRM: connecting fragments found in receptor molecules.
A novel algorithm for the connecting of fragment molecules is presented and validated for a number of test systems. Within the CONFIRM (Connecting Fragments Found in Receptor Molecules) approach a pre-prepared library of bridges is searched to extract those which match a search criterion derived from known experimental or computational binding information about fragment molecules within a target binding site. The resulting bridge 'hits' are then connected, in an automated fashion, to the fragments and docked into the target receptor. Docking poses are assessed in terms of root-mean-squared deviation from the known positions of the fragment molecules, as well as docking score should known inhibitors be available. The creation of the bridge library, the full details and novelty of the CONFIRM algorithm, and the general applicability of this approach within the field of fragment-based de novo drug design are discussed.
Thompson
David C
DC
Wyeth Research, Chemical and Screening Sciences, 200 CambridgePark Drive, Cambridge, MA, 02140, USA.
Denny
R Aldrin
RA
Nilakantan
Ramaswamy
R
Humblet
Christine
C
Joseph-McCarthy
Diane
D
Feyfant
Eric
E
D000465:Algorithms; D001665:Binding Sites; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D019809:Streptavidin / Q000737:chemistry
D008024:Ligands; D020033:Protein Isoforms; D011506:Proteins; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D019809:Streptavidin