The GPCR drug discovery group led by Jana Selent, is focused on the functionality of G protein coupled receptors (GPCRs) in the context of CNS-related disorders taking into account: receptor plasticity, activation mechanism, signaling bias, ligand binding, the effect of the membrane and other interaction partners. The final goal is to translate obtained molecular insights into the design of drug candidates with improved therapeutic profiles.
- In-silico Multi-Receptor Profiling of Antipsychotic Drugs. The clinical efficacy of antipsychotic drugs has been ascribed to a complex interplay consisting of multiple targets (particularly G protein-coupled receptors, GPCRs) and multiple mechanisms (e.g. signaling bias, receptor crosstalk) which together determine a distinct pattern of cell signaling. In this context, our group focuses on deciphering molecular mechanism of this complex interplay of current antipsychotic drugs that are responsible for their clinical efficacies. Finally, we aim on the discovery of novel pharmacological interventions and the design of new lead structures for antipsychotic therapy.
- GPCR Dimers as Drug Target for the Treatment of Schizophrenia. Recent studies have described receptor dimerization as relevant mechanism for signaling mediated by GPCRs. We study this phenomenon in the context of antipsychotic drug action. Our group provides support for the design of bivalent ligands that selectively target a specific GPCR dimer. On one hand, such molecular probes are extremely useful to interrogate the contribution of dimers to psychotic conditions. On the other hand, such probes allow us validating the usefulness of GPCR dimers as drug target for the treatment of schizophrenia. Once a target is validated, we apply diverse computational tools to obtain first small drug like molecules (structure-based/ligand-based) towards this target.
- Membrane Lipid-Mediated Effects on GPCR signaling. The lipid composition of cell membranes can modulate the function of key membrane proteins such as G protein-coupled receptors (GPCRs). As several diseases have suggested to alter relevant biophysical properties of membranes such as density or fluidity, it has become a research priority to understanding the role of membrane environment on the dynamics and function of GPCRs. We address this important question by studying direct and indirect membrane effects on receptor monomers and dimers using all-atom as well as coarse grained simulation setups.
- Database for GPCR dynamics. The main mission of this project is to provide dynamic insights into crystallized receptors at a public-accessible platform. Main features include deposition /storage of MD data, query tools, visualization of MDs for relevant features as well as basic analysis tools. Importantly, the database is designed to allow not only MD experts but also chemoinformaticians or medicinal chemists to easily browse and use dynamic information on GPCRs. GPCRmd will be integrated into the established and well-known GPCRdb database (http://gpcrdb.org/). This integration will ease the process of gaining popularity and accelerating the deposition of new MD simulations and can make an important contribution to the finding of new drugs towards this important target class. More info here.