CombiDOCK: Structure-based combinatorial docking and library design

We have developed a strategy for efficiently docking a large combinatorial library into a target receptor. For each scaffold orientation, all potentia l fragments are attached to the scaffold, their interactions with the recep tor are individually scored and factorial combinations of fragments are con structed. To test its effectiveness, this approach is compared to two simpl e control algorithms. Our method is more efficient than the controls at sel ecting best scoring molecules and at selecting fragments for the constructi on of an exhaustive combinatorial library. We also carried out a retrospect ive analysis of the experimental results of a 10 x 10 x 10 exhaustive combi natorial library. An enrichment factor of approximately 4 was found for ide ntifying the compounds in the library that are active at 330 nM.