This project progressed beyond the state of the art by developing techniques that enable very efficient fragment-based discovery of GPCR ligands by performing structure-based virtual screening of large chemical libraries. In the applied part of the project, the rational design of polypharmacology is the most significant achievement. A common property of drugs (e.g. antipsychotics) is that such compounds interact with multiple targets, which is essential for their therapeutic effect. However, the fact that multi-target interactions may be required for treatment of complex diseases contrasts with the philosophy of modern drug discovery, which focuses on ligands with selectivity for a one target. Although potential of polypharmacology is clear, progress has been limited by difficulties to rationally design such compounds. We undertook the challenge to design ligand polypharmacology relevant for Parkinson’s disease. The project successfully used structure-based modelling to design a single compound with the ability to modulate the activity of two GPCRs. The most potent dual-target compounds display high potency at both targets and one scaffold was demonstrated to be active in a rat model of parkinsonism.