PSDI 2018 "26th Protein Structure Determination in Industry Meeting"

Previously, the drug mode-of-action for enzymatic protein targets was aimed at the catalytic center for substrate competition. Meanwhile, alternative modes of inhibitions are applied to address typical inhibitor challenges such as selectivity, efficacy and resistance formation. Less conserved interaction sites are now targeted by the means of allosteric inhibitors, which are also independent from high cellular substrate concentrations. Protein-protein-interaction inhibitors are generated that block the complex formation between the target proteins and the associated functional proteins. In addition inhibitor residence time, together with kinetic selectivity, became an important optimization parameter so that inhibitors selective for distinct activation states of enzymes can be engineered. Further on, covalent inhibitors are designed to attack specific residues within the target protein. Such recent drug discovery advancements require fundamental changes in the pool of appropriate assays, biophysics and screening tool boxes and implementation. Proteros biostructures has established stand-alone and integrated discovery service solutions that combine biochemistry with innovative biophysics and protein crystallography to facilitate both, efficient and data driven generation of innovative novel inhibitors. The Proteros drug discovery services platform enables to screen specifically for allosteric inhibitors. Assays are established to identify compounds blocking relevant protein-protein interactions. Proteros’ high throughput binding assays allow screening for inhibitors addressing non-activated enzyme states. Proteros’ high throughput kinetic profiling provides knowledge about both binding affinity and binding kinetics against on- and off-kinase targets for all involved compounds to facilitate the rapid generation of residence time optimized inhibitors. Methods are in place that de-convolute the binding of covalent inhibitors into a) non-covalent and b) covalent contribution to escape resistance formation. Whereas protein crystallography discloses different binding modes and enables medicinal chemistry to improve the inhibitor properties. The workshop demonstrates the application and synergistic use of such different discovery service technologies for an efficient integrated drug discovery process towards innovative inhibitors.