Importance of the field: The generation of new chemical leads as a starting point for drug development is a critical step in pharmaceutical drug discovery. High-throughput screening and the attached processes have rapidly evolved over the past few years to become one of the main sources for new leads by testing large compound libraries for activity against a target of interest in biochemical in vitro tests using the recombinant protein or cell-based assays. Very recently, the traditional functional assay read-out technologies are being complemented by biophysical methods which directly measure the physical interaction (affinity) between a low molecular weight compound and a target protein. These technologies are receiving increasing attention and application for affinity screening and increasingly complement and augment the more classical activity screens. Today, such biophysical techniques are applied in hit identification as well as later stages such as hit validation, optimization and lead optimization phase.
Areas covered in this review: This review focuses on the principle and application of selected affinity-based screening technologies, especially those which increasingly have been used in different phases of the lead finding process over the past few years. Furthermore, we highlight how throughput, robustness and information content of the discussed methods guide and determine their impact in lead finding and how to make the best use of them.
What the reader will gain: The reader will gain an insight into the very broad spectrum of biophysical affinity screening methods and its high potential to support the generation of new leads. As a consequence, the reader will be able to judge which affinity method is of advantage at a certain lead discovery phase.
Take home message: Biophysical methods are very powerful tools to identify new hits and/or validate/optimize a hit to a lead. Those technologies often offer novel ways of screening complementing available classical screening technologies. An integrated, holistic approach using the combination of functional read-out technologies with different biophysical methods enables a project team to efficiently promote and progress the most promising chemotypes.