Combinatorial chemistry in drug discovery

Abstract

Several combinatorial methods have been developed to create focused or diverse chemical libraries with a wide range of linear or macrocyclic chemical molecules: peptides, non-peptide oligomers, peptidomimetics, small-molecules, and natural product-like organic molecules. Each combinatorial approach has its own unique high-throughput screening and encoding strategy. In this article, we provide a brief overview of combinatorial chemistry in drug discovery with emphasis on recently developed new technologies for design, synthesis, screening and decoding of combinatorial library. Examples of successful application of combinatorial chemistry in hit discovery and lead optimization are given. The limitations and strengths of combinatorial chemistry are also briefly discussed. We are now in a better position to truly leverage the power of combinatorial technologies for the discovery and development of next-generation drugs.

Figure 1

Overview of combinatorial technologies. The various combinatorial technologies are shown in orange (diverse and focused libraries) and black (focused small library), the nature of chemical compounds is shown in blue, and the two broad groups of screening assays are shown in green. Depicted within the red ovals are the screening assays and nature of library compounds pertaining to each technology. The question mark indicated that, in practice, synthetic planar microarray is limited to peptides and simple oligomers.

Figure 2

Strategy for generating side chain-to-tail macrocyclic peptides in vitro in a pH-triggered manner or directly in living cells.

Figure 3. OB2C combinatorial library technology for the discovery of death ligands

A: Structure of an OB2C combinatorial library bead (an example). B: A cartoon illustrates the OB2C concept. C: A snapshot of a positive bead (indicated by a red arrow, stained with anti-cleaved caspase 3 antibody) from an OB2C library. D: Structures of representative death ligands identified from OB2C libraries. LWK1: peptide; S7-Y: peptidomimetic; LLS2: small-molecule.