Doty Scientific Inc

An Hr-mas H/f/x/y Uhf NMR Probe for Allosteric Drug Research at Physiological Conditions - an Hr-mas H/f/x/y Uhf NMR Probe for Allosteric Drug Research at Physiological Conditions Abstract More Than a Third of Drugs in Development Include a Fluorinated Site, and a Large Fraction Target Allosteric Sites (for Reduced Side Effects) in Macromolecules. NMR Is Generally the Most Powerful Tool for Getting Essential Chemical, Functional, and Dynamical Information on Drug-protein Interactions, But Conventional Liquids- NMR Methods Are Not Effective on Large Proteins. Fast-mas Ssnmr Methods Have Produced Spectra From Solid Macromolecule Samples With Improved Resolution, But Fast-mas Is Not Well Suited for Acquiring Data at Physiological Conditions, Which Is Crucially Important, Particularly for Drugs Targeting Allosteric Sites. the Optimum Method for Acquiring High Resolution (HR) NMR Spectra From Inhomogeneous Samples – Such as Tissues, or Proteins Solubilized in a Bicelle or Nano-disc in a Saline Hydrated Lipid Environment – at Near- Physiological Conditions Is Hr-mas, Which Among Other Things Requires Larger Sample Volumes (because Concentration Is So Low) and Ultra-low E Fields During 1H Decoupling at High Fields. Hr-mas 1H NMR Has Demonstrated Resolution of 15 PPB on Smaller Peptides in Bicelles and 4 PPB on Various Metabolites in Cells. However, Hr-mas Probes With 1H/19F Capability Have Apparently Never Been Reported. Some H/F/X Mas Probes Have Been Demonstrated Up to 700 MHZ, But the Best Resolution Reported Thus Far in Such Is ~200 PPB. for Solution NMR on the Other Hand, Four-channel Multinuclear 1H/19F/X/2H Probes Are Available to at Least 800 MHZ, and Such Have Proven to Be Extremely Valuable for Identification and Characterization (using 1H/15N, 19F/13C, and 19F/2H/15N Methods) of Active Fragments, Their Binding to Soluble Proteins, and Their Effects on Soluble Protein-protein Interactions. the Problem Is That Such Methods Don’t Work With Insoluble Proteins – as Involved in Cancers, Alzheimer’s Disease (ad), Parkinson’s Disease (PD), and Many Others. This Phase-i Proposal Seeks Funding to Develop, Build, and Test a Prototype H/f/x/y Hr-mas Probe With a Novel RF Circuit Optimized for High-sensitivity 19F Detection, With Detection or Simultaneous High-power RF Irradiation on Any or All the Other Three Channels for Further Narrowing Beyond That Usually Seen in Hr-mas, as Mas Alone Doesn’t Average J-couplings. the Probe Will Be Suitable for Hr-mas – on Liquids, Semi-solids, Tissues, and Solids – at Fields From 7-28 T With Rotor Diameters From 1.3 MM to 3 MM. the Novel Probe Would Allow the Full Suite of NMR Acquisition and Automated Structure Determination Protocols Developed for Solution NMR to Be Applied to Fluorinated Drugs Targeting Allosteric Sites in Macromolecules. the Phase-i 3-MM Probe Is Expected to Achieve 5 PPB Resolution at Near-physiological Conditions, and the Phase-ii Probe ~3 PPB, or About Two Orders of Magnitude Better Than Prior Published H/F/X Mas Data. the Probe Will Be Essentially Devoid of Problematic Background Signals for All the Primary Nuclides (1H, 19F, 31P, 13C, 2H, 14N, and 17O), and It Will Be Tunable to Virtually All Combinations of Interest, Thereby Making It Also Invaluable in Such Areas as Metabolism, Materials Science, Catalysis, and Sustainable Energy.