How high-throughput medicinal chemistry can expedite lead discovery, lead optimization, and beyond

High-throughput medicinal chemistry (HTMC) plays a pivotal role in lead discovery and optimization, especially to improve efficiency in the synthesis of library compounds. It originated in Combinatorial Chemistry in the early 1990s and evolved to date as a powerful tool in drug discovery. This efficient tool promotes the rapid generation of both relevant molecules and potential drug candidates, and is widely used in pharmaceuticals, biotechnology, and other chemistry-related discovery programs. HTMC has resulted in the rapid expansion of compound libraries to keep pace with the demands of high-throughput screening. The ability to do novel chemistry in multistep parallel synthesis of privileged structures in both the solution and solid phase has allowed for the creation of diverse chemical libraries in high quality and purity. Efficient synthesis of well-designed compound libraries requires a knowledge-based strategy of both solution-and solid-phase syntheses with appropriate combinations of both.1,2 Well-designed privileged scaffolds and lead-like or drug-like compound libraries should contain diverse sets of templates and building blocks that bear sufficient functionality to address and answer critical questions of structure-activity relationships (SARs). In this case, a high success rate of the library is also essential. Screening well-designed small-molecule libraries that utilize drug-relevant building blocks and biologically privileged scaffolds can provide better coverage of drug-like chemically accessible space, which will enhance the probability of successful lead discovery.