Enumeration and Visualization of Large Combinatorial Chemical Libraries

Abstract

The advent of combinatorial chemical library synthesis and, more recently, DNAencoded chemical library synthesis offers drug discovery researchers access to billions of unique chemical entities that can be useful candidates for screening against therapeutic drug targets. This chapter provides a brief overview of methods and tools that are currently available to enumerate and analyze very large combinatorial chemical libraries of more than one billion members. A combinatorial chemical library produced from a four-component Ugi reaction serves to illustrate some practical considerations for enumeration and analysis. The application of cheminformatics tools to select building blocks, enumerate library products, and also calculate several key molecular properties to profile the library is discussed. At the end of the chapter, several methods such as heat maps, to compare chemical space for four compound libraries, either qualitatively through visualization or quantitatively, with molecular similarity calculations are suggested.