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G protein-coupled receptors (GPCRs) are integral membrane proteins responsible for signal transduction of extracellular stimuli into the cell. Because of their widespread distribution throughout the human body and important roles in physiological processes, GPCRs are prominent drug targets and approximately 34% of all approved drugs interact with members of this superfamily. GPCR ligands are used as drugs against various diseases, including neurodegenerative and neuropsychiatric disorders. The increased availability of GPCR structural information has enhanced understanding of GPCR function but also enables structure-based drug design (SBDD). This thesis focuses on SBDD targeting allosteric and orthosteric binding sites of GPCRs and strategies to identify multi-target ligands. Drug discovery campaigns are traditionally based on the one-target-one-drug paradigm, but effective treatment of complex neurological disorders generally requires modulation of several signaling pathways. In publication I, dual-target ligands that activate the D₂ dopamine receptor (D₂R) and antagonize the A_2A adenosine receptor (A_2AAR) were designed through a structure-based approach. Both GPCRs are relevant for Parkinson’s disease (PD) and animal studies support that interactions with these targets induce neuroprotection while eliciting a synergistic therapeutic effect. One of the designed ligands was shown to yield an antiparkinsonian effect in a rodent model. Publication II focuses on the identification of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu₅) using structure-based virtual screening. Such modulators have been considered as a treatment of PD, fragile X syndrome and depression. The study discovered 11 allosteric modulators and four of these were also shown to be NAMs of mGlu₅. Manuscript III describes the development of dual-target ligands acting as antagonists of the A_2AAR and NAMs of mGlu₅. Blocking the activity of both receptors has been shown to have a synergistic antiparkinsonian effect that could be both symptomatic and neuroprotective. In this study, virtual screening was used to discover drug-like compounds with submicromolar binding affinity to both targets. Publication IV presents a comprehensive review of SBDD targeting GPCRs of all classes with a specific focus on the method of molecular docking. Publication V describes a program for automatic validation of X-ray crystal structures. Possible applications involve assessment of protein structures used in SBDD or the generation of high-quality test sets for the evaluation of molecular docking methods. The results of this thesis illustrate that structure-based virtual screening is a versatile tool to discover ligands with tailored pharmacological properties.