GABAB Receptor Positive Allosteric Modulators: Novel Approaches for Drug Design and Discovery

The GABAB receptor plays a crucial role in the central nervous system by mediating neurotransmission of GABA, the main inhibitory neurotransmitter. Dysfunction associated with the receptor function has been linked to various diseases and neuropsychiatric disorders, making it a highly relevant drug target over the past decades. Traditionally, drug discovery campaigns targeting the GABAB receptor have focused on the discovery and development of ligands targeting the binding site of the endogenous ligand (the orthosteric site). However, targeting the allosteric binding sites of the GABAB receptor has emerged as a new and promising approach for developing more selective drugs with improved therapeutic effects as multiple cryo-EM structures of the full GABAB receptor have become available and have even led to the identification of a new allosteric binding site. The recent availability of full GABAB receptor structures provides an excellent starting point for applying methods relying heavily on structure data, such as computer-aided molecular simulations and structure-based drug design, to increase our understanding of allosteric interactions as well as discovery and development of new positive allosteric modulators targeting the receptor.