NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

Yu, Jun-lan; Chen, Tiantian; Zhou, Chen; Lian, Fulin; Tang, Xu-long; Wen, Yi; Shen, Jingkang; Xu, Yechun; Xiong, Bing; Zhang, Nai-Xia

doi:10.1038/aps.2016.19

Cited by 17 publications

(14 citation statements)

References 43 publications

(57 reference statements)

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“…Bromodomains are epigenetic regulatory domains, inhibition of which has therapeutic implications for cancer, heart disease, and inflammation 24,25 and are often targeted in fragment-screening campaigns. 26–28 For these studies, Brd4 was biosynthetically 19 F-labelled using the amino acid precursor 5-fluoroindole at all three tryptophan sites (W75, W81, and W120; Figure 1A) due to the enrichment of aromatic amino acids at protein-protein interaction interfaces. 13,29 When small molecules or ε-acetylated histone substrates bind to Brd4, we have observed a significant perturbation of the W81 resonance, which is located in the binding pocket.…”

Section: Resultsmentioning

confidence: 99%

Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening

et al. 2016

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Protein-observed 19F (PrOF) NMR is an emerging tool for ligand discovery. To optimize the efficiency of PrOF NMR experiments, paramagnetic relaxation enhancement through the addition of chelated Ni(II) was used to shorten longitudinal relaxation time without causing significant line broadening. Thus enhancing relaxation time leads to shorter experiments without perturbing the binding of low- or high-affinity ligands. This method allows for time-efficient screening of potential ligands for a wide variety of proteins in the growing field of fragment-based ligand discovery.

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Section: Resultsmentioning

confidence: 99%

Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening

et al. 2016

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“…For conventional proton-based NMR screening, multiple fragments with no significant proton signal overlapping are pooled into one group to improve the screening efficiency. In our lab, to generate our own fragment library, all of the small compounds in the ZINC database were filtered according to the modified RO3 [ 70 ]. Then, to cover a broader chemical space, the resulting fragments were clustered into groups according to their structural similarities, and only those cluster-center compounds were selected and purchased for fragment library construction [ 70 ].…”

Section: Nmr In Fragment-based Drug Discoverymentioning

confidence: 99%

Applications of Solution NMR in Drug Discovery

Shi

Zhang

2021

Molecules

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During the past decades, solution nuclear magnetic resonance (NMR) spectroscopy has demonstrated itself as a promising tool in drug discovery. Especially, fragment-based drug discovery (FBDD) has benefited a lot from the NMR development. Multiple candidate compounds and FDA-approved drugs derived from FBDD have been developed with the assistance of NMR techniques. NMR has broad applications in different stages of the FBDD process, which includes fragment library construction, hit generation and validation, hit-to-lead optimization and working mechanism elucidation, etc. In this manuscript, we reviewed the current progresses of NMR applications in fragment-based drug discovery, which were illustrated by multiple reported cases. Moreover, the NMR applications in protein-protein interaction (PPI) modulators development and the progress of in-cell NMR for drug discovery were also briefly summarized.

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“…Ligand-based NMR screening was also used to evaluate a library of 539 fragments against the first bromodomain of BRD4 (BRD4(I)) [60]. The fragments were screened as mixtures of 8-10 compounds at 200µM against 20µM of BRD4(I).…”

Section: Citationmentioning

confidence: 99%

“…The positive hits within each mixture were then confirmed by a second round of ligand-based NMR using individual compound. From the screen, 10 hits were identified and five fragments (at 100µM) were capable of displacing the fluorescence-labeled benzodiazepine inhibitor from BRD4(I) in a fluorescence anisotropy assay [60]. Both protein-observed NMR and X-ray crystallography showed that the fragment hits bound to the AcK binding pocket of BRD4(I) and thus could be used as starting points for developing high affinity inhibitors.…”

Section: Citationmentioning

confidence: 99%

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Young

Chang

2017

MOJBB

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Cancer is associated with epigenetic changes such as abnormal DNA methylation and histone tail modifications, and these changes result in tumor suppressor gene silencing, oncogene overexpression, and genome instability -phenomena that are closely linked to cancer development. The epigenetic marks on DNA and histones are reversible and therefore it is possible to restore normal patterns through chemically targeting epigenetic regulators that generate, maintain, recognize, and remove these marks. In recent years, fragment-based drug discovery (FBDD) has been used to target both the protein-protein interactions (PPI) as well as the enzymatic functions of epigenetic factors. Low molecular weight fragments (MW<300) efficiently sample chemical space and can bind to discreet binding pockets on target proteins such as those found on PPI interface. In this review, we describe the biophysical, biochemical, and in silico methods used for FBDD. We also discuss the examples of using FBDD to target epigenetic readers such as bromodomain-containing proteins and epigenetic enzymes such as arginine methyltransferases 6 (PRMT6), lysine demethylase 4 (KDM4), and Sirtuin 2 (SIRT2). FBDD provides an economical alternative to traditional high throughput screening. Effective FBDD endeavors depend heavily on gaining structural information of ligand-protein interactions early on and the close collaboration between biophysicists, chemists, and biologists in all stages of the drug discovery process. Using FBDD, protein-protein interactions in non-enzymatic epigenetic factors can potentially be chemically modulated. Furthermore, FBDD enables the identification of new binding pockets that can improve compound specificity against various epigenetic enzymes.

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NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

Cited by 17 publications

References 43 publications

Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening

Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening

Applications of Solution NMR in Drug Discovery

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

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NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

Cited by 17 publications

References 43 publications

Paramagnetic relaxation enhancement for protein-observed 19F NMR as an enabling approach for efficient fragment screening

Paramagnetic relaxation enhancement for protein-observed 19F NMR as an enabling approach for efficient fragment screening

Applications of Solution NMR in Drug Discovery

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

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Product

Resources

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Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening

Paramagnetic relaxation enhancement for protein-observed ¹⁹F NMR as an enabling approach for efficient fragment screening