Recent progress in fragment-based drug discovery facilitated by NMR spectroscopy

Wang, Lei; Gao, Jia; Ma, Ronghua; Liu, Yaqian; Liu, Mingqing; Zhong, Fumei; Hu, Jie; Shu-ju, LI; Wu, Jihui; Jiang, Hualiang; Zhang, Jiahai; Ruan, Ke‐He

doi:10.1016/j.mrl.2021.100025

Cited by 9 publications

(2 citation statements)

References 126 publications

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“…The use of NMR spectroscopy as a quantitative technique stemmed from the fact that the area under a peak in the NMR spectra is usually proportional to the number of spins involved, giving an absolute quantitation or the actual amount of compound contained within the sample [34,35]. Information on certain molecules such as functional groups, topology, dynamics, and three-dimensional structure in solution and solid state could be obtained with nuclear magnetic resonance (NMR) spectroscopy [36,37]. In the 1H NMR of the used ChCl-AA, integration of the peak at approximately δ 2.0 ppm, characteristic of acetic acid, revealed a gradual decrease in peak area with the increasing number of cycles that the DES had gone F I G R E 5 of 1H NMR peak at δ 2.0 ppm (acetic acid), δ 3.3 ppm (choline chloride), and δ 1.4 ppm (ferulic acid) in recovered choline chloride-acetic acid (ChCl-AA) after each extraction.…”

Section: Resultsmentioning

confidence: 99%

Recycling of deep eutectic solvent in the extraction of ferulic acid from oil palm empty fruit bunch

Ng,

Nu'man,

Hasliyanti

2024

J of Separation Science

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The study explored ferulic acid extraction from palm empty fruit bunch (EFB) fiber using deep eutectic solvent (DES) of chlorine chloride—acetic acid as the extraction medium and the way to recover and recycle the DES thereafter. Antisolvent was added to selectively precipitate the ferulic acid, which was recovered by filtration thereafter. Recycling the DES without further purification led to increased ferulic acid yield with each subsequent extraction, likely due to retained ferulic acid. The retained ferulic acid and other impurities could be removed by precipitation brought upon by the addition of a second antisolvent. 1H nuclear magnetic resonance revealed that there was no excess ferulic acid in the recycled DES‐treated with two types of antisolvents (ethanol and water). The yield of ferulic acid increased from 0.1367–0.1856 g/g when treated with only one antisolvent to 0.1368–0.2897 g/g with two antisolvent treatments. Oil droplets were also observed in the DES upon the addition of antisolvent 2, with recovered oil ranging from 0.6% to 3%. The study emphasized the significance of using DES as an extraction medium for ferulic acid from oil palm EFB fiber and the method to recycle the DES for subsequent processes.

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Section: Resultsmentioning

confidence: 99%

Recycling of deep eutectic solvent in the extraction of ferulic acid from oil palm empty fruit bunch

Ng,

Nu'man,

Hasliyanti

2024

J of Separation Science

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“…To clarify this issue, we aimed to discover inhibitors with new chemotypes and evaluate their antiproliferative capability in AF9-sensitive cells. Herein, we identified four small-molecule hits against the AF9 YEATS domain using NMR fragment-based screening [ 30 , 31 ]. The complex crystal structure revealed the key interactions between one of these hits and the AF9 YEATS domain.…”

Section: Introductionmentioning

confidence: 99%

Fragment-Based Discovery of AF9 YEATS Domain Inhibitors

Liu

Jin

Lü

et al. 2022

IJMS

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YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.

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How to Find a Fragment: Methods for Screening and Validation in Fragment‐Based Drug Discovery

Kirkman,

dos Santos Silva,

Tosin

et al. 2024

ChemMedChem

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Fragment‐based drug discovery (FBDD) is a crucial strategy for developing new drugs that have been applied to diverse targets, from neglected infectious diseases to cancer. With at least seven drugs already launched to the market, this approach has gained interest in both academics and industry in the last 20 years. FBDD relies on screening small libraries with about 1000‐2000 compounds of low molecular weight (about 300 Da) using several biophysical methods. Because of the reduced size of the compounds, the chemical space and diversity can be better explored than large libraries used in high throughput screenings. This review summarises the most common biophysical techniques used in fragment screening and orthogonal validation. We also explore the advantages and drawbacks of the different biophysical techniques and examples of applications and strategies.

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Recent progress in fragment-based drug discovery facilitated by NMR spectroscopy

Cited by 9 publications

References 126 publications

Recycling of deep eutectic solvent in the extraction of ferulic acid from oil palm empty fruit bunch

Recycling of deep eutectic solvent in the extraction of ferulic acid from oil palm empty fruit bunch

Fragment-Based Discovery of AF9 YEATS Domain Inhibitors

How to Find a Fragment: Methods for Screening and Validation in Fragment‐Based Drug Discovery

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