Fragment‐Based Lead Generation

Fragment-based methods are an integral part of the drug discovery toolbox. This chapter outlines some of the assays used for fragment hit identification before exploring strategies and tactics employed in hit optimization. NMR is one of the fragment-based screening methods that can be classified into two main categories namely protein-detected and ligand-detected. Biochemical assays can offer a strong advantage where dynamics of the protein may be critical, such as for G protein coupled receptors (GPCRs). The chapter also focuses on hit validation that is a critical step in fragment-based lead generation (FBLG). The most widely used approach for evaluating fragments is ligand efficiency, defined as the binding energy divided by the number of nonhydrogen atoms in the molecule. Fragments are suited for protein-protein interactions (PPIs) because they can bind to the relatively small pockets available on a protein surface.