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.

Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biological target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biological target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, we performed a druggability assessment for each target family reported in KTGS, calculated the pocket properties, and used them to extract possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall we conclude that the KTGS approach is universal and could be used without restrictions regarding the physicochemical properties of the addressed pocket.

Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC...

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address...

In this review, we analyze the enzyme DXS, the first and rate-limiting protein in the methylerythritol 4-phosphate pathway. This pathway was discovered in 1996 and is one of two known metabolic pathways for the biosynthesis of the universal building blocks for isoprenoids. It promises to offer new targets for the development of anti-infectives against the human pathogens, malaria or tuberculosis. We mapped the sequence conservation of 1-deoxy-xylulose-5-phosphate synthase on the protein structure and analyzed it in comparison with previously identified druggable pockets. We provide a recent overview of known inhibitors of the enzyme. Taken together, this sets the stage for future structure-based drug design.

The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a “fork-like” motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for MtDXPS through structure-based drug design.

Acylhydrazone‐based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone‐based inhibitors of the aspartic protease endothiapepsin as a follow‐up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X‐ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit‐to‐lead optimization in future acylhydrazone‐based DCC projects.

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