Discussion

The importance of the dissociation rate, koff, (or residence time τ =1/koff) in drug discovery has recently gained increasing prominence. Indeed it has been our experience that the primary gains in potency as a series progresses has largely been due to increased residence time. For simple binary systems, such as a ligand-protein complex koff is a uni-molecular process, independent of concentration, solely dependent on time. We have exploited this fundamental feature and the concept of group efficiency to assess crude unpurified reactions to identify the target molecules with significant improvements in koff. This achieves several aims; improving hits-to-lead turn-around times, significant saving in material costs and permits more fragment and hit series to be exploited for the same resource. We will demonstrate the utility of this approach using SPR with retrospective examples from HSP90 and PIN1 The usefulness of this approach will be further demonstrated with prospective examples from the targets PDHK1 and TNKS2.