Fragment-based drug discovery using NMR spectroscopy

Harner, Mary J.; Frank, Albin; Fesik, Stephen W.

doi:10.1007/s10858-013-9740-z

Cited by 188 publications

(196 citation statements)

References 77 publications

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“…Notably, the 34 kDa CXCR1 chemokine G protein-coupled receptor (GPCR) structure was elucidated by rotationally aligned (RA) solid-state NMR [21]. NMR also has an important role to play in investigating protein-protein, and ligand-protein interactions as well as for fragment-based drug discovery [24][25][26].…”

Section: Nmrmentioning

confidence: 99%

Overcoming bottlenecks in the membrane protein structural biology pipeline

Hardy

Bill

Jawhari³

et al. 2016

Biochemical Society Transactions

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Correspondence to: Alice Rothnie (+44 121 204 4013 a.rothnie@aston.ac.uk) or Anass Jawhari (+33 649 555 606 ajawhari@calixar.com) Key words:Membrane proteins Structural biology SMALP Calixarenes MNG Solubilisation Abbreviations:EM-Electron Microscopy GPCR-G protein-coupled receptors GNG-Glucose Neopentyl Glycol MSP -Membrane Scaffold Protein MNG-Maltose Neopentyl Glycol NMR-Nuclear magnetic resonance SMA-Styrene Maleic Acid SMALPs -SMA Lipid Particles AbstractMembrane proteins account for a third of the eukaryotic proteome, but are greatly underrepresented in the Protein Data Bank. Unfortunately, recent technological advances in X-ray crystallography and electron microscopy cannot account for the poor solubility and stability of membrane protein samples. A limitation of conventional detergent-based methods is that detergent molecules destabilize membrane proteins, leading to their aggregation. The use of orthologues, mutants and fusion tags has helped improve protein stability, but at the expense of not working with the sequence of interest. Novel detergents such as GNG, MNG and calixarene-based detergents can improve protein stability without compromising their solubilising properties. SMALPs focus on retaining the native lipid bilayer of a membrane protein during purification and biophysical analysis.Overcoming bottlenecks in the membrane protein structural biology pipeline, primarily by maintaining protein stability, will facilitate the elucidation of many more membrane protein structures in the near future.

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Section: Nmrmentioning

confidence: 99%

Overcoming bottlenecks in the membrane protein structural biology pipeline

Hardy

Bill

Jawhari³

et al. 2016

Biochemical Society Transactions

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“…[2] However,t argeting PPIs can be difficult owing to their large hydrophobic binding surfaces. [3] There are currently three commonly employed approaches to develop modulators of PPIs: [4] fragment screening, [5] computational screening and drug design, [6] and the exploration of peptides and peptidomimetics. [7] However,c omputational design and fragment screening require large libraries of molecules and extensive synthetic work, often resulting in non-selective compounds.…”

Section: Protein-proteininteractions(ppis)regulatemanyprocessesmentioning

confidence: 99%

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

2017

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Targeting PPIs with small molecules can be challenging owing to large,h ydrophobic binding surfaces. Herein, we describe as trategy that exploits selective a-helical PPIs,transferring these characteristics to small molecules.The proof of concept is demonstrated with the apoptosis regulator Mcl-1, commonly exploited by cancers to avoid cell death. Peptide-directed binding uses few synthetic transformations, requires the production of asmall number of compounds,and generates ahigh percentage of hits.Inthis example,about 50 % of the small molecules prepared showed an IC 50 value of less than 100 mm, and approximately 25 %h ad IC 50 values below 1 mm to Mcl-1. Compounds show selectivity for Mcl-1 over other anti-apoptotic proteins,possess cytotoxicity to cancer cell lines,a nd induce hallmarks of apoptosis.T his approach represents an ovel and economic process for the rapid discovery of new a-helical PPI modulators.

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“…This has given rise to increased interest in fragment screening and then fragmentbased drug design (FBDD), in which the molecules screened generally conform to the Rule of 3 rather than the well-known Rule of 5. 18 These fragment molecules are generally below molecular weight 300 Da, with a calculated partition coefficient clogP <3 and less than 3 hydrogen bond donors. The advantages of using fragments are that (i) fragment chemical space is much much smaller than drug space because of the smaller molecular size and it can thus be covered more completely with a reasonably sized library, (ii) fragments tend to be more promiscuous in their binding than larger molecules because they are unencumbered with lots of side chains and appendages that get in the way of a good binding interaction, and (iii) there is a perception that the ligand efficiency (binding energy per heavy atom) of fragments is higher than that of conventional, larger ligands, although in our experience that is not always the case.…”

Section: New Applications Of Nmr Spectroscopy In Pharmaceutical Randdmentioning

confidence: 99%

“…Utilizing fast pulsing methods, it has been reported that more than 200 2-D heteronuclear correlation NMR spectra can be recorded in 24 h using a 500 MHz NMR spectrometer with a cryoprobe, 40 μM protein concentration and a relatively small, globular protein of 15 kDa. 18 These general methods can also be applied to the study of protein-carbohydrate interactions 19 and to the study of complexes with membrane proteins 20 ( Figure 6). This is an exciting and important area, and the first drug emerging from a fragment-based drug discovery approach, Vemurafenib (Figure 7), was approved in 2011.…”

Section: New Applications Of Nmr Spectroscopy In Pharmaceutical Randdmentioning

confidence: 99%

Drug Discovery and Development: the Role of NMR

Everett

2015

eMagRes

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NMR spectroscopy has been a technology of fundamental importance to drug discovery and development for the past 40-50 years, principally through its use in the structure elucidation of leads, drugs, their synthetic intermediates, and the degradation products and impurities of those drug molecules. In the past 30 years, another major area of application of NMR spectroscopy has been metabolic profiling or metabonomics studies of drug metabolism, drug safety, drug efficacy, and disease, through studies of biological fluids such as urine and plasma, representing a change in application from the chemical to the biological sciences. This trend has continued with significant progress in the application of in vivo MRI and magnetic resonance spectroscopy (MRS) to the study of disease states and their treatment in patients and in animal models. More recently, new applications of NMR spectroscopy have emerged such as hit-finding and hit-to-lead optimization, impacting directly on these early stages of the drug discovery process. Finally, the discovery of completely new areas, led by NMR spectroscopy, such as pharmacometabonomics, holds out the promise of improvements in personalized medicine in the future. This article will briefly cover all of these areas, and more, as a prelude to more detailed treatments in the following articles of this work.

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Fragment-based drug discovery using NMR spectroscopy

Cited by 188 publications

References 77 publications

Overcoming bottlenecks in the membrane protein structural biology pipeline

Overcoming bottlenecks in the membrane protein structural biology pipeline

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

Drug Discovery and Development: the Role of NMR

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