Our research projects focus on understanding G protein-coupled receptors (GPCRs) at the molecular level and development of methods for structure-based drug design. We try to develop modeling approaches that can be applied to any receptor. For this reason, we work on a large number of different targets, e.g. adenosine, dopamine, neurotensin, protease-activated, and frizzled receptors. Our projects are often carried out in close collaboration with experimentalists in the research field or pharmaceutical companies.
Currently we are performing research in the following areas:
Structure-based virtual screening & chemical libraries
We perform large-scale molecular docking screening of several hundred million molecules against GPCR structures to predict novel drug candidates. Predicted ligands are purchased or synthesized in our laboratory, followed by testing for activity by experimental collaborators. We are both interested in orthosteric and allosteric modulators of GPCRs, with focus on designing selective and multi-target ligands.
We also develop novel methodology in this area and fragment-based drug design approaches. We are working on improving the physics-based scoring functions used in molecular docking and development of tools that enable rapid exploration of drug-like chemical space.
Structure-guided ligand optimization
We are combining molecular dynamics free energy calculations with medicinal chemistry to design novel GPCR ligands with high selectivity and tailored signaling properties. Predicted ligands are evaluated for bioactivity by experimental collaborators.
GPCR structure prediction
We are developing homology modeling techniques to predict GPCR structure and complexes with ligands at atomic resolution. Such tools are extremely valuable as structural information is still lacking for a majority of the GPCR family.
Activation mechanism of GPCRs
We are using molecular dynamics simulations to simulate how ligand binding can induce conformational changes that lead to receptor activation. We are particularly interested in how ligand binding can lead to signaling via different intracellular pathways.
Role of dimerization in GPCR function
We are combining pharmacological experiments combined with molecular modeling to understand if and how allosteric receptor-receptor interactions influence GPCR signaling.