ABSTRACT
In the past two decades, the field of combinatorial chemistry has experienced several cycles of evolution. In the mid-1980s, Geysen1 and Houghten2 demonstrated the effectiveness of combinatorial synthesis by preparing large numbers of peptides using solid-phase synthetic techniques pioneered by Merrifield.3 Peptide leads were quickly identified and optimized for various molecular targets,
including ligands for transmembrane receptors and inhibitors for enzymes.4 In the 1990s, the field of combinatorial chemistry grew exponentially. Numerous techniques and instrumentation platforms were developed for high-throughput synthesis and purification. This enabled chemists to carry out more complex organic syntheses in parallel fashion, both on solid supports and in solution, to prepare libraries of non-peptide small molecules.5,6 The design of these libraries was typically based on chemistries that were amenable to solid-phase organic synthesis or reactions in solution to furnish the final products in a few steps with high overall yield and purity, rather than directed toward any specific protein target. These large libraries of random compounds brought to drug discovery the promise of rapid hit identification against seemingly any target. Computational techniques were often employed to select the building blocks to enhance the molecular diversity around any given template to increase the probability of producing hits for a variety of targets.7 The increased chemistry throughput in combination with high-throughput screening generated leads and accelerated the overall drug discovery process, resulting in many successful examples for both lead discovery and lead optimization.8 Nowadays, combinatorial chemistry has become an integral tool for medicinal chemists. Small and focused libraries are routinely designed and synthesized for lead identification and optimization against a given target.9 In particular, the positional scanning strategy pioneered by Houghten has proven very effective in identifying ligand segments, from large mixtures of peptides and peptide mimetics, that contribute to the observed biological activity.10 This approach simplifies the deconvolution process associated with mixture-based libraries, and, more importantly, provides structure-activity-relationship (SAR) information for the design of follow-up libraries. This method has been successfully applied to many projects and a wide range of targets.11,12 This chapter describes in detail another successful application of solid-phase combinatorial synthesis, namely, in the discovery of small-molecule leads for the inhibition of adenine nucleotide translocase (ANT).13 Using an analogous approach to positional scanning, we were able to follow SAR trends based on weak activity. Through library iterations, several novel ANT ligands, with comparable affinity to natural product leads, were identified.
