Abstract

Due to their central importance in many physiological processes, membrane proteins are drug targets for around 60% of all approved drugs. Structure based drug discovery on soluble proteins is managed well within the project timelines and portfolio changes in pharmaceutical industry, but transmembrane proteins remain a significant challenge because of their difficulty to be expressed, purified and made them work for full exploration in structure based drug design and high resolution three dimensional structure of complexes with potential drug molecules.
Examples will include the X-ray structure determination of the chemokine receptor CCR2, an emerging target for inflammation, arthritis and oncology by serial X-ray crystallography. Here we explore structural details of ligand binding at the orthosteric and allosteric binding sites to address challenges on drug efficacy and specificity.
X-ray free electron lasers give more physiologically relevant data on protein flexibility at the ligand binding site. Femtosecond X-ray pulses enable monitoring and capturing of dynamic processes of ligand binding and associated conformational changes with great impact to the design of candidate drug compounds.
Furthermore, high resolution cryo-EM structures show increasing impact in drug design due to advances in feasibility of proteins as well as structural resolution. Presentation examples include the human TRPV with bound small molecule agonist as well as a transporter protein validated as antibiotics drug target.