NMR in Target Driven Drug Discovery: Why Not?

Overview

Journal J Biomol NMR

Publisher Springer

Specialties Molecular Biology
Nuclear Medicine

Date 2020 Sep 9

PMID 32901320

Citations 7

Authors

Sebastien Keiffer

Marta G Carneiro

Johan Hollander

Masakazu Kobayashi

Denys Pogoryelev

Eiso Ab

Stephan Theisgen

Gerhard Muller

Gregg Siegal

Affiliations

Soon will be listed here.

Abstract

No matter the source of compounds, drug discovery campaigns focused directly on the target are entirely dependent on a consistent stream of reliable data that reports on how a putative ligand interacts with the protein of interest. The data will derive from many sources including enzyme assays and many types of biophysical binding assays such as TR-FRET, SPR, thermophoresis and many others. Each method has its strengths and weaknesses, but none is as information rich and broadly applicable as NMR. Here we provide a number of examples of the utility of NMR for enabling and providing ongoing support for the early pre-clinical phase of small molecule drug discovery efforts. The examples have been selected for their usefulness in a commercial setting, with full understanding of the need for speed, cost-effectiveness and ease of implementation.

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References

Roberts . Applications of NMR in drug discovery. Drug Discov Today. 2000; 5(6):230-240. DOI: 10.1016/s1359-6446(00)01479-3. View

Tjernberg A, Markova N, Griffiths W, Hallen D . DMSO-related effects in protein characterization. J Biomol Screen. 2006; 11(2):131-7. DOI: 10.1177/1087057105284218. View

Skora L, Mestan J, Fabbro D, Jahnke W, Grzesiek S . NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors. Proc Natl Acad Sci U S A. 2013; 110(47):E4437-45. PMC: 3839726. DOI: 10.1073/pnas.1314712110. View

Pritisanac I, Degiacomi M, Alderson T, Carneiro M, Ab E, Siegal G . Automatic Assignment of Methyl-NMR Spectra of Supramolecular Machines Using Graph Theory. J Am Chem Soc. 2017; 139(28):9523-9533. DOI: 10.1021/jacs.6b11358. View

Heightman T, Callahan J, Chiarparin E, Coyle J, Griffiths-Jones C, Lakdawala A . Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction. J Med Chem. 2019; 62(9):4683-4702. DOI: 10.1021/acs.jmedchem.9b00279. View

Schmidt E, Guntert P . A new algorithm for reliable and general NMR resonance assignment. J Am Chem Soc. 2012; 134(30):12817-29. DOI: 10.1021/ja305091n. View

Dyson H, Wright P . Elucidation of the protein folding landscape by NMR. Methods Enzymol. 2005; 394:299-321. DOI: 10.1016/S0076-6879(05)94011-1. View

Vanwetswinkel S, Heetebrij R, van Duynhoven J, Hollander J, Filippov D, Hajduk P . TINS, target immobilized NMR screening: an efficient and sensitive method for ligand discovery. Chem Biol. 2005; 12(2):207-16. DOI: 10.1016/j.chembiol.2004.12.004. View

Shuker S, Hajduk P, Meadows R, Fesik S . Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996; 274(5292):1531-4. DOI: 10.1126/science.274.5292.1531. View

10.

Wang T, Lucey J . Use of multi-angle laser light scattering and size-exclusion chromatography to characterize the molecular weight and types of aggregates present in commercial whey protein products. J Dairy Sci. 2003; 86(10):3090-101. DOI: 10.3168/jds.S0022-0302(03)73909-5. View

11.

Dehner A, Furrer J, Richter K, Schuster I, Buchner J, Kessler H . NMR chemical shift perturbation study of the N-terminal domain of Hsp90 upon binding of ADP, AMP-PNP, geldanamycin, and radicicol. Chembiochem. 2003; 4(9):870-7. DOI: 10.1002/cbic.200300658. View

12.

Kuntz I, Chen K, Sharp K, Kollman P . The maximal affinity of ligands. Proc Natl Acad Sci U S A. 1999; 96(18):9997-10002. PMC: 17830. DOI: 10.1073/pnas.96.18.9997. View

13.

Dobson C, Evans P, Williamson K . Proton NMR studies of denatured lysozyme. FEBS Lett. 1984; 168(2):331-4. DOI: 10.1016/0014-5793(84)80273-2. View

14.

Pellecchia M, Bertini I, Cowburn D, Dalvit C, Giralt E, Jahnke W . Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov. 2009; 7(9):738-45. PMC: 2891904. DOI: 10.1038/nrd2606. View

15.

Nitsche C, Otting G . NMR studies of ligand binding. Curr Opin Struct Biol. 2017; 48:16-22. DOI: 10.1016/j.sbi.2017.09.001. View

16.

Ma R, Wang P, Wu J, Ruan K . Process of Fragment-Based Lead Discovery-A Perspective from NMR. Molecules. 2016; 21(7). PMC: 6273320. DOI: 10.3390/molecules21070854. View

17.

Hajduk P, Huth J, Fesik S . Druggability indices for protein targets derived from NMR-based screening data. J Med Chem. 2005; 48(7):2518-25. DOI: 10.1021/jm049131r. View

18.

Gossert A, Jahnke W . NMR in drug discovery: A practical guide to identification and validation of ligands interacting with biological macromolecules. Prog Nucl Magn Reson Spectrosc. 2016; 97:82-125. DOI: 10.1016/j.pnmrs.2016.09.001. View

19.

Homans S . NMR spectroscopy tools for structure-aided drug design. Angew Chem Int Ed Engl. 2004; 43(3):290-300. DOI: 10.1002/anie.200300581. View

20.

Ishima R, Torchia D . Protein dynamics from NMR. Nat Struct Biol. 2000; 7(9):740-3. DOI: 10.1038/78963. View