Development and mechanistic studies of an optimized receptor for trimethyllysine using iterative redesign by dynamic...

A new small molecule receptor, A2N, has been identified that binds specifically to trimethyllysine (Kme3) with sub-micromolar affinity. This receptor was discovered through the iterative redesign of a monomer known to incorporate through dynamic combinatorial chemistry (DCC) into a previously reported receptor for Kme3, A2B. In place of monomer B, the newly designed monomer N introduces an additional cation-π interaction into the binding pocket, resulting in more favorable binding to Kme3 by 1.3 kcal mol(-1), amounting to a 10-fold improvement in affinity and a 5-fold improvement in selectivity over Kme2. This receptor exhibits the tightest affinity and greatest selectivity for KMe3-containing peptides reported to date. Comparative studies of A2B and A2N provide mechanistic insight into the driving force for both the higher affinity and higher selectivity of A2N, indicating that the binding of KMe3 to A2N is both enthalpically and entropically more favorable. This work demonstrates the ability of iterative redesign coupled with DCC to develop novel selective receptors with the necessary affinity and selectivity required for biological applications.