Understanding Allostery to Design New Drugs

This chapter provides a critical overview of the current understanding of allosteric regulation. It provides examples of how this can be integrated with structural knowledge, binding site identification methods, and drug design approaches in the discovery of novel biologically active hits. Allostery constitutes the basis underlying major regulatory mechanisms of function: from transcription control to activation and modulation of signaling pathways, cell death, and metabolism. The chapter presents a critical overview of specific approaches integrating diverse lines of investigation into a consistent framework that may help bridge the understanding of protein structure and dynamics with the design of allosteric functional modulators. Molecular chaperones are a class of highly conserved proteins that play a pivotal role in folding, stabilization, degradation, and general quality control of the proteome. G protein-coupled receptors (GPCRs) are naturally allosteric systems, as they function by propagating extracellular stimuli to the cell interior by means of a conformational transition.