NMR in target driven drug discovery: why not?
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PERSPECTIVE
NMR in target driven drug discovery: why not? Sébastien Keiffer1 · Marta G. Carneiro1 · Johan Hollander1 · Masakazu Kobayashi1 · Denys Pogoryelev1 · Eiso AB1 · Stephan Theisgen1 · Gerhard Müller2 · Gregg Siegal1,3 Received: 16 May 2020 / Accepted: 17 August 2020 © The Author(s) 2020
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. Keywords Small molecule drug discovery · Biophysics · Structure based drug design · Fragment based drug discovery
Introduction Some twelve years ago one of us contributed to a far-reaching perspective describing a number of powerful ways in which NMR can contribute to the early stages of developing new small molecule drugs (Pellecchia 2008). In the intervening years, NMR has become an ever more deeply embedded part of our drug discovery process (Glas, et al. 2019; Carneiro 2017; Pritisanac 2017; Chaikuad 2016). However, the use of NMR outside of synthetic chemistry remains confined to a subset of large pharmaceutical companies. In this short perspective, we provide a number of examples in which relatively simple NMR experiments routinely provide us with data critical to the setup of new programs, interpretation of biophysical and biochemical data and elucidation of structural information describing the proteinsmall molecule interaction. Many of these examples will seem obvious to the reader, and yet we observe over and * Gregg Siegal [email protected] 1
ZoBio, JH Oortweg 19, 2333CH Leiden, Netherlands
2
Gotham GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany
3
Amsterdam Institute of Molecular and Life Sciences, Free University Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
over again that the fundamental importance of this type of information is often neglected. These experiments have been selected based on realistic criteria, that is they should: minimize protein consumption, be robust and maximize throughput. The ligand observed experiments do not require particularly high field strength, but an automated sample changer is a must and a cryoprobe is highly desirable. Lastly, the data should be readily interpretable and therefore actionable. Partly, this depends on the skill of the operator in both creatively designing the experiment and
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