Unprecedented speed and success rate with delivering ligand-bound GPCR structures

Modern drug discovery greatly benefits from knowledge of how a drug interacts with its molecular drug target. Membrane protein drug targets represent a significant challenge for high-resolution three-dimensional structure determination limiting the discovery and development of novel medicines. leadXpro AG successfully tackles the membrane protein structure identification challenge to advance the drug discovery process and bring better drugs to the market.

Drug discovery, as we know it today, is an interdisciplinary endeavor. Chemistry, pharmacology, microbiology, and biochemistry shape its course and bring it to a level where new drugs are no longer generated by the imagination of chemists but are a result of an interdisciplinary dialogue of sciences. The understanding of the mechanisms of action, facilitated by the knowledge of biological structure and function, gives rise to the creation of improved chemical structures.

As of today, the structure of only 30 out of 800 membrane proteins has been determined

The diversity of biological targets (enzymes, transporters and channels, G protein-coupled receptors (GPCRs), etc.) and their structures is still a challenge for drug discovery. For example, structures of only 30 out of 800 known human membrane proteins are currently determined and can be used in structure-based drug discovery. In addition, the process of structure determination can take years to accomplish and requires deep knowledge and expertise.

An emerging biotech company at PARK INNOVAARE, leadXpro AG is building a membrane protein structure determination platform. By applying state-of-the-art equipment and methods, such as the synchrotron (SLS), the X-ray free electron laser (SwissFEL) and, in collaboration with the University of Basel, single particle electron microscopy (cryo EM), the company strives to identify new lead compounds with unprecedented specificity and efficacy, uncovering new allosteric mechanisms of action.

Unprecedented speed and details in structure determination

On May 2, 2017, leadXpro AG announced the successful delivery of a multiple GPCR structure determination milestone. In collaboration with a major pharmaceutical company, the leadXpro team was able to identify novel ligand-bound GPCR structures with a great variety of binding modes, with unprecedented speed. The entire process took only four months. “This success story validates our approach and serves as a great example for how we can impact drug discovery programs via collaborative research effort with partner organizations,” says Professor Dr. Michael Hennig, CEO and co-founder of the company.

Now the collaboration partner is leveraging the exquisite structural detail of eleven high-resolution GPCR-ligand co-structures in their drug discovery campaigns. Using this information, chemists can better understand how the compound interacts with the molecular drug target and optimize its properties, resulting in more effective drugs with fewer side-effects.