Issue 36, 2014

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
16 六月 2014
Accepted
24 七月 2014
First published
31 七月 2014

Org. Biomol. Chem., 2014,12, 7059-7067

Author version available

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

N. K. Pinkin and M. L. Waters, Org. Biomol. Chem., 2014, 12, 7059 DOI: 10.1039/C4OB01249F

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements