Dynamic Combinatorial Chemistry: A New Methodology Comes of Age

Abstract

Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental set-ups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.

Optimized Inhibitors of MDM2 via an Attempted Protein‐Templated Reductive Amination

“…Following the design of the initial inhibitor, we generated a combinatorial library by using aldehyde 3 as a core scaffold and eight different amines (4)(5)(6)(7)(8)(9)(10)(11) to explore and fill the extended Leu26 pocket in the best manner and give rise to a focused SAR (Scheme 1).…”

“…In these templated fragment ligations, the target selects its own inhibitors by assembling the corresponding binders from a library of complementary building blocks or by binding and amplifying them from a library of compounds formed in a covalent bond‐forming reaction. In KTGS, the biological target accelerates the irreversible reaction between complementary building blocks upon binding, whereas in DCC a reversible reaction between building blocks affords a dynamic combinatorial library (DCL) from which the biological target selects and amplifies the best binder(s) . Both techniques hold the potential to accelerate drug discovery and are still relatively underexplored, especially in terms of target scope and availability of biocompatible reactions.…”

“…In KTGS, the biological target accelerates the irreversible reaction between complementary building blocks upon binding, [2,3] whereas in DCC a reversible reaction between building blocks affords a dynamic combinatorial library (DCL) from which the biological target selects and amplifies the best binder(s). [4,5] Both techniques hold the potential to accelerate drug discovery and are still relatively underexplored, especially in terms of target scope and availability of biocompatible reactions.…”

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

“…[21][22][23] This minireview covers our work on ptDCC and provides the key features of our protocol, explaining the essential steps in designing a successful ptDCC experiment. Several reviews and book chapters on tdDCC have been published in recent years.…”

Second generation DNA-encoded dynamic combinatorial chemical libraries

“…18 The chemical analogue of dynamic recombination has been realized in the DNA-encoded dynamic combinatorial chemical library (EDCCL). 15 As a variation of a dynamic chemical library, 20 EDCCL was designed as intrinsically unstable DNA duplexes, in order to combat the problem of low signal-to-noise ratios and high incidences of false positives associated with most of the large libraries. 21,22 In the absence of a target protein binding, randomly paired encoded chemical moieties undergo constant reshuffling in solution.…”