Our research operates at the dynamic multidisciplinary interface of synthetic organic chemistry, medicinal chemistry, chemical biology, and structural biology. The core mission of our laboratory is to decipher the molecular mechanisms of transmembrane signaling and to translate these insights into the design of novel, highly precise therapeutic entities. Our group has pioneered innovative concepts in drug discovery, focusing extensively on G protein-coupled receptors (GPCRs)—the largest class of cell-surface receptors and primary targets for modern pharmacology—as well as other challenging membrane proteins and ion channels.
By combining state-of-the-art synthetic methodology and molecular pharmacology with structural biology and advanced computational studies, our research is structured around four interconnected, high-impact pillars:
1. Structure-Based Drug Design & Target-Directed Chemical Synthesis
A cornerstone of our research is the synergetic combination of structural biology and functional studies with target-directed organic synthesis. Our laboratory actively investigates the atomic-resolution blueprints of active and inactive receptor states determined by cryogenic electron microscopy (cryo-EM) to resolve complex macromolecular structures. These precise structural insights serve as the direct foundation for our core expertise: the design and chemical synthesis of novel small-molecule ligands. While the computational screening of ultra-large virtual libraries is accomplished through a powerful network of international collaboration partners, our group focuses on translating in silico hits into tangible, highly optimized chemical entities. This integrated workflow allows us to systematically explore novel chemical spaces, resulting in the structural elucidation and discovery of unprecedented chemotypes targeting class A GPCRs, Frizzled receptors, and challenging non-GPCR targets like the CFTR ion channel.
2. Functional Selectivity, Biased Agonism & Next-Generation Therapeutics
A central milestone of our recent research is the exploitation of receptor structural plasticity to achieve functional selectivity (biased signaling). Classical drugs often activate all downstream pathways of a receptor indiscriminately, frequently leading to dose-limiting side effects. We design „biased ligands“ capable of stabilizing specific receptor conformations that preferentially engage distinct intracellular transducers (e.g., activating G protein pathways while avoiding beta-arrestin recruitment, or vice versa). This paradigm allows us to decouple desired therapeutic efficacy from adverse on-target toxicity. Our efforts have successfully yielded highly innovative, functionally selective agonists for opioid, serotonin 1A (5-HT1A), and alpha2 adrenergic receptors, paving the way for novel, non-addictive, and safer treatments for chronic pain and neuropsychiatric disorders.
3. Allosteric Modulation, Bitopic Design & Polypharmacology
Achieving absolute subtype selectivity within highly conserved receptor families remains one of the greatest challenges in medicinal chemistry. To circumvent the limitations of orthosteric binding sites, our group focuses intensely on the design of allosteric and bitopic (dual-steric) ligands. By targeting less-conserved allosteric topography or intracellular binding pockets, we can fine-tune receptor signaling with unprecedented precision. Furthermore, we expand these concepts into the realm of custom-tailored polypharmacology, engineering single small molecules that exhibit defined multi-target profiles to combat complex, multi-factorial diseases. Our structural and dynamic investigations into neurotensin, muscarinic acetylcholine, and adrenergic receptors continuously redefine the boundaries of spatial and temporal selectivity.
Nat. Chem. Biol. 2020, 16, 749-755. [doi>10.1038/s41589-020-0549-2]
4. Chemical Biology, Photopharmacology & Advanced Molecular Probes
To visualize, quantify, and manipulate receptor dynamics in real time and within complex biological environments, we develop highly sophisticated molecular tools:
Photopharmacology: We synthesize photoswitchable (photopharmacological) and light-activated covalent ligands, enabling the spatial and temporal control of receptor signaling using specific wavelengths of visible light.
Fluorescent Probes: Our lab designs high-affinity, dually labeled fluorescent ligands optimized for advanced single-molecule microscopy, allowing the direct observation of receptor monomerization, dimerization, and intracellular trafficking in living cells.
Radiopharmacy & Molecular Imaging: In close cooperation with preclinical imaging centers, we develop novel radioligands (including 18F-, 99mTc-, and Lutetium-complexed DOTA derivatives) targeting orexin and neurotensin receptors, serving as powerful diagnostic and therapeutic tools (theranostics) in oncology and neurology.
Covalent ligands: Covalent ligands are designed to form permanent chemical bonds with GPCRs, providing prolonged target engagement and enhanced receptor selectivity. Additionally, they serve as vital tools in structural biology to stabilize specific, flexible receptor conformations for advanced imaging and crystallization.
Through the integration of target-directed synthesis, structural biology, and deep functional pharmacology, our group aims to shape the future of targeted precision medicine and contribute fundamentally to the global understanding of molecular pharmacology.