Towards fully integrated ultrafast drug discovery by NMR
Hyperpolarized nuclear magnetic resonance (NMR) holds immense promise for drug discovery. We are excited to present a fully automated, end-to-end, fragment-based lead discovery ultrafast NMR platform leveraging photoinduced hyperpolarization.
Utilizing our recently developed photoinduced fragment library and our fully automated light-coupled NMR platform (Cryolight), we can screen up to 700 samples daily.(1, 2) The Cryolight technology is plug-and-play, enabling the automation of hyperpolarized NMR fragment screening and affinity determination using a sample changer. Cryolight performs equally on low-field benchtop spectrometers (60-80 MHz), an economical alternative to high-field NMR that does not require liquid helium or dedicated facilities.(3, 4)
Hyperpolarized fragments can be screened within a few seconds at low micromolar concentrations, enabling a throughput of several hundred samples per day.(2) In conjunction with our automated data analysis software, results are available in real time. Furthermore, ligand-based binding epitopes can be inferred directly from screening data, revealing early structural information that can be used for docking experiments. In the next step, we show how the affinity of a protein-ligand interaction can be obtained within 15 minutes using the light-induced NMR method, which allows the characterization of up to 50 systems daily.(5) Due to the strong sensitivity enhancement of up to 1000-fold for the fragments, hyperpolarization can also reveal structural information of the bound ligand or the complex. We tested our platform on several targets, including PIN1, K-Ras, and PKG1, for which we present our findings.
In summary, we present the first fully operational hyperpolarized NMR drug discovery platform, comprising screening, affinity determination, and structure determination, compatible with commercially available automated high and low field spectrometers.