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

Abstract

Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.

A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate

“…26 Protein-templated dynamic combinatorial chemistry (DCC) is an elegant method for the identification of potent ligands from a combinatorial library of building blocks with suitable linking chemistry in presence of a given protein. 27,28 To apply this method to LecA, we introduced hydrazides at the para-or meta-position of phenyl b-D-galactoside in order to allow for acylhydrazone formation in DCC. For this purpose, we chose two galactoside building blocks with meta-or para-attached hydrazides, 1m and 1p, and varied linker length, rigidity and number of rotatable bonds by systematically increasing the number of methylene units in the corresponding benzaldehyde spacers B-F.…”

Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar‐Based Molecules that Target Bacterial Glucosyltransferase

“…Other factors could result in false‐positive or false‐negative hits such as concentration and purity of the protein template, buffer composition, and binding interaction (aggregation) between the DCL members [31] . To avoid such pitfalls, we used low concentration of purified GTF180 (0.1 equivalent to the building blocks) and selected the optimum buffer and pH for DCC according to our systematic stability monitoring [20] . Furthermore, we used cheminformatics to exclude potential aggregators from the DCLs through the aggregator advisor [32] …”

“…Due to the change in equilibrium in presence of a protein, good binders get amplified and will therefore be selected as hits (Figure 2). The conditions, reactions, protocols, analysis and applications of DCC were reviewed before [17–20] . For example, the group of Lehn et al.…”

Hit-Optimization Using Target-Directed Dynamic Combinatorial Chemistry: Development of Inhibitors of the Anti-Infective Target 1-Deoxy-D-Xylulose-5-Phosphate Synthase

“…Considering the stability issues of drDXS at lower pH and the slow acylhydrazone formation at neutral pH, the use of aniline as a nucleophilic catalyst was required. 16,17 The template effect of drDXS on the dynamic combinatorial library (DCL) was evident by comparing it with the blank DCC experiment (without protein) using LC-MS/MS analysis. Selection of initial dynamic combinatorial library.…”