In the ERC Synergy project Highly Informative Drug Screening by Overcoming NMR Restrictions (HiSCORE) the research team will develop an information-rich high-throughput drug screening methodology.
Kentgens “This is a tremendous recognition for the methodological developments we have been working on in the last decade. This grant gives us the necessary support to bring these developments to the next level; making massive parallel NMR detection of small sample quantities possible and thus boosting application areas such as drug discovery.”
The need for drug screening with increasingly higher throughput is dictated by both the increasing number of drug targets made available through genomics and the increasing number of chemical molecules generated through combinatorial chemistry. Merely Boolean high-throughput screening techniques today can scan large compound libraries, but the ever-increasing throughput has not translated into a significant increase in late-phase drug candidates. The HiSCORE project presents a synergistic approach to high-throughput, high-information drug screening that builds on the complementary skills of four laboratories supported by two external experts of drug screening.
The research team will focus on developing NMR methodology that will enable the efficient discovery of viable candidate drug molecules, with specific binding properties, in a physiologically relevant environment. HiSCORE will focus on rapid determination of relevant drug characteristics, such as reliable determination of binding constants (KD) to relevant proteins, the half maximal inhibitory concentration (IC50) which is a measure of the potency of a substance in inhibiting a specific biological or biochemical function., and the pharmacometabolomic characteristics of a drug molecule under biologically relevant conditions. To achieve this with sufficient throughput, ground-breaking advances in NMR methodology are needed.
Kentgens : “HiSCORE merges together the most innovative branches in the field of NMR hyperpolarization, microcoils, microfluidics, parallel acquisition, and machine learning. To bring this all together is very challenging, and requires the specific expertise of all partners, but should eventually allow us to overcome the current shortcomings of NMR based drug screening and enable full characterization of up to 100,000 compounds within weeks. Our contribution builds on our expertise in the field of micro-resonator design, the development of dynamic nuclear polarization (DNP) in a microfluidic context and para-hydrogen induced polarization (PHIP). A major challenge is to develop an approach that allows hyperpolarisation of molecules in a generic way and push signal enhancement to its quantum limits. Another hurdle is to design massive arrays of parallel detectors that allow multiple experiments simultaneously that can be uniquely decoded without interfering with each other.”