Highly Informative Drug Screening by Overcoming NMR Restrictions

ongoing

The need for drug screening with increasingly higher throughput is dictated both by 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. HiSCORE 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: (i) Research and build innovative magnetic resonance instrumentation (Kentgens, IMM/RU) that can provide small, hyperpolarized solid samples on a seconds timescale, transfer and dissolve or liquefy these samples with minimum dilution, and acquire multiple high-resolution NMR spectra of the liquefied samples in parallel (Meier, IBG/KIT), using complementary contrast-enhancement methods, in up to 1000 massively parallelized microfluidic detectors (Korvink, IMT/KIT). (ii) Use this instrumentation for binding assays and measure the dissociation constants in the nano to micromolar range, and determine kinetic rates of the association and dissociation for a large number of complexes of putative drug compounds and protein targets (Bodenhausen, ENS) (iii) Use this instrumentation for functional assays, in particular for systems that comprise multiple enzyme steps with intermediate products, and to determine the efficacy of potential inhibitors, while fully exploiting the rich information that can be obtained by fluorine-19 NMR. (iv) Use this instrumentation for metabonomic assays to observe the metabolism of the compounds in cultures of living cells in view of identifying potentially toxic side-products. The contrast between compounds that bind to targets and those that fail to bind will be boosted by exploiting long-lived states