Elucidating the molecular mechanism of biased signaling at the serotonin 2A receptor for the design of new-generation neuropsychiatric medications

• Applicant: Dr. Marc André Dämgen
• Subject Area: Biophysics ; Structural Biology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471315262

G-protein-coupled receptors (GPCRs) are the largest class of human membrane proteins and control virtually all aspects of our physiology. More than a third of all drugs rely on interactions with GPCRs for the treatment of a wide range of diseases, including neuropsychiatric disorders, cancer, and Alzheimer’s. Upon binding of extracellular signaling molecules, GPCRs change their shape and couple to intracellular transducer proteins, such as G-proteins and arrestins, which activate different intracellular signaling cascades. The discovery that certain molecules, that bind to the same binding site in a GPCR, can selectively stimulate one GPCR downstream signaling pathway over others (biased signaling/functional selectivity) presents a major opportunity to develop more effective and safer medicines that selectively activate the desired therapeutic pathway while minimizing side effects by not activating undesired pathways. However, the structure-based design of such drugs is impeded by the lack of an atomic-level mechanistic understanding of biased signaling, a quintessential biological mechanism in its own right. The goal of this proposal is to 1. elucidate the molecular mechanism of biased signaling and 2. design biased ligands based on this insight that will serve as lead molecules for future drug development campaigns. The application to the serotonin 2A receptor, a pharmacologically highly important drug target for neuropsychiatric disorders, will have a major impact, as it will enable the rational design of a completely new generation of neuropsychiatric drugs with greater efficacy and fewer side effects. By combining state-of-the-art molecular simulations with complementary experimental approaches, this project bridges mechanistic insight and ligand design, and paves the way for the development of clinically useful therapeutics.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ron Dror