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

Abstract

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.