Dynamic Combinatorial Diversity in Drug Discovery

Abstract

IntroductionCombinatorial chemistry evolved as a key technology for the rapid generation of large populations of structurally distinct molecules that can be screened efficiently en masse for desirable properties. This approach, in combination with highthroughput screening, evolved into a powerful technique capable of significantly accelerating the drug discovery process [1]. Initially developed to produce peptide libraries for screening against antibodies or receptors, combinatorial synthesis and the screening of combinatorial arrays became an integral part in lead generation and optimization in drug discovery [2][3][4][5]. Furthermore, combinatorial methodologies also demonstrated their potential in other areas, such as the development and discovery of catalysts, and material science [6,7].Modern combinatorial libraries are characterized by the generation of numerous different, but structurally related compounds that exist discretely as static entities, under similar conditions, in a systematic manner. Currently, there are several distinct methodologies for the generation of combinatorial libraries [8,9]. These combinatorial arrays can be produced in a parallel fashion, either as a library of individual compounds or as pooled mixtures. In applying a parallel format, the compounds are handled individually in separated compartments. This removes difficulties associated with compound mixtures; and it allows for every individual compound a straightforward evaluation of chemical integrity and structure-activity relationship after biological testing. The library size handled with this methodology is more limited than in a pooling strategy. Pooled mixture formation is straightforward and less time-consuming than the synthesis of individual compounds. More difficult is the analysis and screening of mixtures of components. By the split and mix technology, very large libraries can be formed progressively over multiple synthetic steps. Also, several technological advances in solid phase automated synthesis, analysis, robotics and miniaturization allow the rapid parallel synthesis and characterization of very large arrays of individual compounds. The substances generated are then subsequently evaluated for biological activity by high-throughput screening, applying fully automated systems towards a chosen target protein. 341Fragment-based Approaches in Drug Discovery. Edited

Reporter Ligand NMR Screening Method for 2-Oxoglutarate Oxygenase Inhibitors

“…Finally, we applied the 2OG reporter method to inhibitor discovery for hit validation. Protein-directed dynamic combinatorial chemistry (DCC), which is related to the fragment-based drug discovery (FBDD) method, is an emerging technique for inhibitor discovery. − DCC is an approach to the generation and identification of protein ligands via reversible interconversions of simple building blocks in the presence of a target protein template (Figure S24, Supporting Information). Previously, we have successfully applied protein-directed DCC to identify ligands produced by reversible boronate ester formation that led to novel nanomolar inhibitors for PHD2. , This work involved the use of a boronic acid “scaffold”, which binds in the 2OG binding pocket and is a weak inhibitor of PHD2.…”

Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery

“…There is a paradigm shift in the drug discovery community to move away from screening large libraries (e.g., hundreds of thousands of compounds) to the use of alternative screening approaches and focus on much smaller chemical libraries (e.g., a few thousand compounds maximum) [9]. The protein-directed dynamic combinatorial chemistry (DCC) method [10,11,12,13,14,15,16,17,18] and the related fragment-based screening method [19,20,21,22,23] are two examples of these alternative screening approaches, which, when compared to HTS, are relatively inexpensive and allow the exploration of large chemical space in a more efficient manner.…”

“…The concept of protein-directed DCC was coined in the late 1990s by the supramolecular chemistry community [24], and since then, there have been rapid developments in the field. Protein-directed DCC relies on a library of small molecules that can react reversibly with each other to generate chemical diversity [10,11,12,13,14,15,16,17,18]. Early publications have focussed on proof-of-principle studies, which included investigating the types of reversible chemical reactions that are compatible with protein-directed DCC, and the range of biophysical techniques that are suitable for the detection of protein binders from a dynamic and complex mixture.…”