Multiple binding modes of a small molecule to human Keap1 revealed by X‐ray crystallography and molecular dynamics simulation

Satoh, Mikiya; Saburi, Hajime; Tanaka, Tomoyuki; Matsuura, Yoshinori; Naitow, Hisashi; Shimozono, Rieko; Yamamoto, Naoyoshi; Inoue, Hideki; Nakamura, Noriko; Yoshizawa, Yoshitaka; Aoki, Toyohiro; Tanimura, Ryuji; Kunishima, N.

doi:10.1016/j.fob.2015.06.011

Cited by 33 publications

(51 citation statements)

References 63 publications

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“…The binding affinity of AS with BSA was assayed using the SPR-based Biacore T200 (GE Healthcare) at 298 K 37,38. BSA was covalently immobilized on a CM5 gold sensor chip (GE Healthcare) by standard amine-coupling chemistry.…”

Section: Methodsmentioning

confidence: 99%

Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

Lin¹,

Lee²,

Zhang³

et al. 2016

DDDT

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Fenretinide is a novel anticancer agent reported to exhibit anti-invasive and antimetastatic activities. It has also been shown to improve obesity and diabetes, although the effects of fenretinide on hypertension are still unknown, and the detailed mechanisms remain unclear. In this study, we have shown that treatment with lipopolysaccharide (LPS) decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ) in RAW264.7 macrophages, and pretreatment with fenretinide reversed the effect of LPS on PPARγ expression. In addition, LPS-induced pro-inflammatory cytokine production, including tumor necrosis factor-α, interleukin 6, and monocyte chemoattractant protein 1 were dose-dependently reversed by fenretinide, and the effects of fenretinide on LPS-induced pro-inflammatory cytokine production were blocked by treatment with PPARγ antagonist. Moreover, fenretinide decreased LPS-induced inducible nitric oxide synthase expression and nitrogen oxide production. These effects were blocked by the pretreatment with PPARγ antagonist in a dose-dependent manner, indicating fenretinide activated PPARγ to exert anti-inflammation activity. In view of the role of inflammation in hypertension and the anti-inflammatory action of fenretinide, we found that administration of fenretinide in spontaneously hypertensive rats significantly decreased blood pressure. Taken together, these results indicate that fenretinide might be a potent antihypertensive agent that works by suppressing inflammation via activating PPARγ.

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Section: Methodsmentioning

confidence: 99%

Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

Lin¹,

Lee²,

Zhang³

et al. 2016

DDDT

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“…56 Babaoglu and Shoichet deconstructed a -lactamase inhibitor into fragments with 8, 11 and 14 heavy atoms and observed that the fragments did not preserve the binding mode corresponding to the same moiety in the full inhibitor. 57 Satoh et al 58 examples that fragments bound with appropriate overlap with the hot spot of consensus clusters preserve their binding mode, 65 while those bound at the site of other clusters may change their binding mode upon structure expansion. It is also consistent with the fact that although fragments are versatile binders with the ability to bind to various protein targets, they can also be evolved to higher specificity for the more druggable targets.…”

Section: Size and Shape Considerationsmentioning

confidence: 99%

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

et al. 2016

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Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function: it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry, but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.Rules are for the obedience of fools and the guidance of wise men.Harry Day, Royal Air Force (1898-1977

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“…The identification of Nrf2 activators has enticed the attention of researchers around the world as they can be utilized as therapeutic agents against oxidative stress‐related diseases. Two primary mechanisms elicit Nrf2 activation, one being the modification of cysteine residues in Keap1 and another being the disruption of protein‐protein interaction (PPI) between Keap1 and Nrf2 . In this study, we made an attempt to identify Keap1‐Nrf2 PPI inhibitors that disrupt PPI between Keap1a/b and Nrf2 in the zebrafish ( Danio rerio ) model system rather than identifying electrophilic activators, which covalently modify the cysteine residues in the Keap1.…”

Section: Introductionmentioning

confidence: 99%

“…Two primary mechanisms elicit Nrf2 activation, one being the modification of cysteine residues in Keap1 and another being the disruption of protein-protein interaction (PPI) between Keap1 and Nrf2. [15][16][17][18][19][20] In this study, we made an attempt to identify Keap1-Nrf2 PPI inhibitors that disrupt PPI between Keap1a/b and Nrf2 in the zebrafish (Danio rerio) model system rather than identifying electrophilic activators, which covalently modify the cysteine residues in the Keap1. The former is preferred the most due to their less toxic nature over the latter, as the latter modifies thiol groups of other off-target proteins leading to unpredictable toxic effects.…”

mentioning

confidence: 99%

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish

Raghunath

Raju

Sundarraj

et al. 2019

Basic Clin Pharma Tox

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The Keap1‐Nrf2‐ARE system serves as a premier defence mechanism to curb oxidative stress, which remains as one of the major causes of ageing and pathogenesis in various diseases. Nrf2 is the principal master regulator of the cellular defence system, and its activation remains the prospective therapeutic approach against chronic diseases. One of the recent strategies is to disrupt Keap1‐Nrf2 protein‐protein interaction (PPI) that alters the docking of Keap1 with Nrf2 by compounds occupying a position in the Keap1 blocking the interface with Nrf2. In this study, we made an attempt to identify the compounds with anticancer, antioxidant and anti‐inflammatory properties to disrupt Keap1a/b‐Nrf2 PPI through in silico molecular docking in zebrafish. The phylogenetic analysis of Keap1 proteins revealed the existence of orthologous Keap1‐Nrf2‐ARE system in lower vertebrates that includes zebrafish. The DGR domains of zebrafish Keap1a and Keap1b were modelled with Modeller 9.19 using Keap1 of Mus musculus (PDB ID:5CGJ) as template. Based on the docking calculations, top hit compounds were identified to disrupt both Keap1a and Keap1b interaction with Nrf2 which include quercetin 3,4′‐diglucoside, flavin adenine dinucleotide disodium salt hydrate, salvianolic acid A, tunicamycin and esculin. The LC50 of esculin in 3 dpf zebrafish larvae is 5 mmol/L, and the qRT‐PCR results showed that esculin significantly increased the transcription of Nrf2 target genes—Gstpi, Nqo1, Hmox1a and Prdx1 in 3 dpf zebrafish larvae. These potential hits could serve as safer Nrf2 activators due to their non‐covalent disruption of Keap1‐Nrf2 PPI and be developed into efficacious preventive/therapeutic agents for various diseases.

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Multiple binding modes of a small molecule to human Keap1 revealed by X‐ray crystallography and molecular dynamics simulation

Abstract: Graphical abstract

Cited by 33 publications

References 63 publications

Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish

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