Characterization and structure-activity relationship of natural flavonoids as hERG K + channel modulators

Sun, Xiaorun; Xu, Bingyuan; Xue, Yucong; Li, Honglin; Zhang, Huiran; Zhang, Yuanyuan; Kang, Lei; Zhang, Xiaolu; Zhang, Jianping; Jia, Zhanfeng; Zhang, Xuan

doi:10.1016/j.intimp.2017.02.012

Cited by 13 publications

(7 citation statements)

References 23 publications

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“…This may be because quercetin binds to more than one, low-affinity site on each KCNQ channel subunit, as suggested by docking studies herein, whereas E-2-dodecenal appears instead to have one high-affinity site 8 . Nevertheless, the ability of quercetin to augment KCNQ1, KCNQ1-KCNE1 and KCNQ1/KCNE3 activity apparently by binding to the top of the VSD (and especially to R231) and/or F340 in S6 suggests that quercetin represents a novel chemical space for medicinal chemistry development of future KCNQ channel activators that adopt a different augmentation mechanism than other well-known KCNQ activators 7 – 9 , 20 , 26 , 32 , 33 , 35 , 52 , 53 ; this type of development would also be targeted toward avoiding hERG inhibition, a property previously linked to quercetin although the binding site and mechanism were not determined 54 .…”

Section: Discussionmentioning

confidence: 99%

The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator

Redford

Abbott

2020

Commun Biol

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Many commonly consumed plants are used as folk medicines, often with unclear molecular mechanisms. Recent studies uncovered the ubiquitous and influential KCNQ family of voltage-gated potassium (Kv) channels as a therapeutic target for several medicinal plant compounds. Capers - immature flower buds of Capparis spinosa - have been consumed for food and medicinal purposes for millennia. Here, we show that caper extract hyperpolarizes cells expressing KCNQ1 or KCNQ2/3 Kv channels. Capers are the richest known natural source of quercetin, the most consumed dietary flavonoid. Quercetin potentiated KCNQ1/KCNE1, KCNQ2/3 and KCNQ4 currents but, unusually, not KCNQ5. Strikingly, quercetin augmented both activation and inactivation of KCNQ1, via a unique KCNQ activation mechanism involving sites atop the voltage sensor and in the pore. The findings uncover a novel potential molecular basis for therapeutic effects of quercetin-rich foods and a new chemical space for atypical modes of KCNQ channel modulation.

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Section: Discussionmentioning

confidence: 99%

The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator

Redford

Abbott

2020

Commun Biol

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“…al. 53 , Zhang et al 54 , Siramshetty et al 55 , Keseru et al 30 , Doddareddy et al 56 , Sun et al 57 , Pubchem NCATS 58 , Pubchem JHICC 59 , ChEMBL 60 and FDA-Drugs 61 . Datasets from Cai et al, Pubchem NCATS, Pubchem JHICC and ChEMBL are simulated to be the clients who take part in federated training, the rest of those datasets are only simulated as test sets.…”

Section: Data Curation and Partitioningmentioning

confidence: 99%

Facing small and biased data dilemma in drug discovery with federated learning

Xiong

Cheng

et al. 2020

Preprint

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Artificial intelligence (AI) models usually require large amounts of high quality training data, which is in striking contrast to the situation of small and biased data faced by current drug discovery pipelines. The concept of federated learning has been proposed to utilize distributed data from different sources without leaking sensitive information of these data. This emerging decentralized machine learning paradigm is expected to dramatically improve the success of AI-powered drug discovery. We here simulate the federated learning process with 7 aqueous solubility datasets from different sources, among which there are overlapping molecules with high or low biases in the recorded values. Beyond the benefit of gaining more data, we also demonstrate federated training has a regularization effect making it superior than centralized training on the pooled datasets with high biases. Further, federated model customization for each client can effectively help us deal with the highly biased data in drug discovery and achieve better generalization performance. Our work demonstrates the application of federated learning in predicting drug related properties, but also highlights its promising role in addressing the small data and biased data dilemma in drug discovery.

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“…The human voltage‐sensitive K+ channel hERG (human ether‐à‐go‐go‐related gene) is overexpressed in several types of cancer cells, with fisetin to function as hERG K+ channel modulator. C2=C3 double bond was crucial for hERG inhibition, while the hydroxy group in C‐3 was not involved in such an effect (Sun et al, 2017). The catechol group in the B ring appears to play a role as an inhibitor of lipid peroxidation.…”

Section: Structure–activity Relationship Of Fisetinmentioning

confidence: 99%

Recent advances in the biosynthesis, structure–activity relationships, formulations, pharmacology, and clinical trials of fisetin

Zhong

Farag

Chen

et al. 2022

eFood

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Fisetin is one of the most popular flavonoids found in vegetables and fruits with several health benefits such as antidiabetic, anticancer, and anti-inflammatory activities. Biotechnology or chemosynthesis tools were used for the synthesis of fisetin and its analogs to improve their yield and efficacy. Structure activity relationships (SARs) revealed that the aromatic hydroxyl groups especially the 3,4-dihydroxylation at ring B were crucial for fisetin biological activities, whereas substitution of several hydroxyl groups in fisetin appeared to impact its original effects. The ongoing or upcoming clinical trials containing fisetin are applied in drugs and dietary supplements. Noteworthily, fisetin has been successfully incorporated into nutraceuticals in the market. Furthermore, the delivery system of fisetin-loaded nanocochleates showed the best bioavailability compared to other formulations. This review presents the latest research progress of fisetin on its synthesis, structure-activity relationships, pharmacokinetics, biological activities, and underlying mechanisms, bioavailability, delivery systems, and clinical trials to provide a comprehensive insight into the research and application of this valuable natural compound.

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Characterization and structure-activity relationship of natural flavonoids as hERG K + channel modulators

Cited by 13 publications

References 23 publications

The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator

The ubiquitous flavonoid quercetin is an atypical KCNQ potassium channel activator

Facing small and biased data dilemma in drug discovery with federated learning

Recent advances in the biosynthesis, structure–activity relationships, formulations, pharmacology, and clinical trials of fisetin

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