Chapter 3 - Step IIIa: Biological Hit Discovery Through High-Throughput Screening (HTS): Random Approaches and Rational Design

Abstract

Hit discovery requires the rapid identification of biologically active compounds from large and diverse chemical collections. The first section covers the birth and the development of high-throughput screening-HTS, describing target- and phenotype-based assays, and listing assay formats (fluorescence- and luminescence-based, label-free, microfluidics). The following section deals with virtual HTS-vHTS, describing how in silico models of targets and of their putative ligands accelerate hit discovery and reduce its costs. Structure-based and ligand-based drug design is covered in detail, through popular tools and methods (molecular descriptors, fingerprints, pharmacophores, docking, similarity searches). The last section describes fragment-based drug discovery-FBDD and the use of biophysical screening methods (X-ray, NMR, SPR, thermal assays) to simplify the discovery of hits, and their further structural optimization.