Recent advances in understanding the structures and functions of GPCRs are having an enormous impact on the medicinal chemistry community. Indeed, the 2012 Nobel Prize for chemistry was awarded to pioneers of the GPCR field.Stabilized GPCRs (StaRs�) can be crystallized in activated and ground-state conformations during 'live' medicinal chemistry campaigns. Results of some of the first examples of achieving this will be presented, along with structure-based drug design case studies. For example, crystal structures of �1 adrenergic receptor were solved in co-complex with fragment-sized molecules and used to guide the optimization of potent, efficient and novel ligands.For several GPCRs, efficient leads with good drug-like properties have been identified following virtual or fragment screening. In three cases, these have been progressed to a candidate drug in less than 2 years.The process for generating StaRs� will be described, along with their use in fragment and biophysical screening.

Fragment screening and structure-based drug design with G protein-coupled receptors

245th National Meeting (2013)

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