Fragment Evolution For Gpcrs: The Role Of Secondary Binding Sites In Optimization

We developed a docking-based fragment evolution approach that extends orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluating 13 000 extensions for the beta(1)- and beta(2)-adrenergic receptors we synthesized and tested 112 bitopic molecules. Our results confirmed the positive contribution of the secondary binding pocket to both potency and selectivity optimizations.