Exploring Fragment Screening and Optimization Strategies Using Acetylcholine-Binding Protein

Abstract

From a niche area of research that was mainly applied by technology focused research groups in the private sector, fragment-based drug discovery (FBDD) has transformed into a rewarding drug-discovery technology that is applied by almost every major pharmaceutical company. Next to biotech and big pharma, the methodology has also attracted considerable interest from academic research groups that have endorsed fragment-based approaches as a sound scientific approach and an attractive low-cost alternative to high-throughput screening, that enables efficient discovery pathways to novel lead and tool compounds. This chapter describes several studies that were performed in our academic research laboratories and in the labs of our collaborators in which acetylcholine-binding protein (AChBP), a homolog to the ligand-binding domain of Cys-loop receptors, has been used as a robust target to investigate the various aspects of fragment-based approaches, including fragment screening technologies and fragment optimization strategies. Timely concepts such as the combination of structural, kinetic and thermodynamic characterization of ligand-induced conformational changes will be described using this particular target. These studies demonstrate how the fragment-based methodology can be used to increase our understanding of the molecular aspects of ligands and fragments binding to protein binding sites.