Structure-based virtual screening approach to identify novel classes of PTP1B inhibitors

Park, Hwangseo; Bhattarai, Bharat Raj; Ham, Seung Wook; Cho, Hyeongjin

doi:10.1016/j.ejmech.2009.02.011

Cited by 37 publications

(20 citation statements)

References 25 publications

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“…Our approach is supported by reports [40][41][42][43][44] phosphatase inhibitors [41], and angiogenin inhibitors [42] has been enabled through the use of virtual screening strategies.…”

Section: Accepted Manuscriptmentioning

confidence: 96%

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity

Wright¹,

Watson²,

McGuffin³

et al. 2015

The Journal of Nutritional Biochemistry

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Flavonoids reduce cardiovascular disease risk through anti-inflammatory, anti-coagulant and anti-platelet actions. One key flavonoid inhibitory mechanism is blocking kinase activity that drives these processes. Flavonoids attenuate activities of kinases including phosphoinositide-3-kinase, Fyn, Lyn, Src, Syk, PKC, PIM1/2, ERK, JNK and PKA. X-ray crystallographic analyses of kinase-flavonoid complexes show that flavonoid ring systems and their hydroxyl substitutions are important structural features for their binding to kinases. A clearer understanding of structural interactions of flavonoids with kinases is necessary to allow construction of more potent and selective counterparts. We examined flavonoid (quercetin, apigenin and catechin) interactions with Src family kinases (Lyn, Fyn and Hck) applying the Sybyl docking algorithm and GRID. A homology model (Lyn) was used in our analyses to demonstrate that high-quality predicted kinase structures are suitable for flavonoid computational studies. Our docking results revealed potential hydrogen bond contacts between flavonoid hydroxyls and kinase catalytic site residues. Identification of plausible contacts indicated that quercetin formed the most energetically stable interactions, apigenin lacked hydroxyl groups necessary for important contacts and the non-planar structure of catechin could not support predicted hydrogen bonding patterns. GRID analysis using a hydroxyl functional group supported docking results. Based on these findings, we predicted that quercetin would inhibit activities of Src family kinases with greater potency than apigenin and catechin. We validated this prediction using in vitro kinase assays. We conclude that our study can be used as a basis to construct virtual flavonoid interaction libraries to guide drug discovery using these compounds as molecular templates.

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“…Our approach is supported by reports [40][41][42][43][44] phosphatase inhibitors [41], and angiogenin inhibitors [42] has been enabled through the use of virtual screening strategies.…”

Section: Accepted Manuscriptmentioning

confidence: 96%

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity

Wright¹,

Watson²,

McGuffin³

et al. 2015

The Journal of Nutritional Biochemistry

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show abstract

“…It has been successfully used to predict high affinity protein ligands (Lee et al, 2010;Park et al, 2009). The molecules of the library are ranked according to their predicted binding affinity for the receptor.…”

Section: Introductionmentioning

confidence: 99%

Consensus virtual screening approaches to predict protein ligands

Kukol

2011

European Journal of Medicinal Chemistry

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-In order to exploit the advantages of receptor-based virtual screening, namely time/cost saving and specificity, it is important to rely on algorithms that predict a high number of active ligands at the top ranks of a small molecule database. Towards that goal consensus methods combining the results of several docking algorithms were developed and compared against the individual algorithms. Furthermore, a recently proposed rescoring method based on drug efficiency indices was evaluated. Among AutoDock Vina 1.0, AutoDock 4.2 and GemDock, AutoDock Vina was the best performing single method in predicting high affinity ligands from a database of known ligands and decoys. The rescoring of predicted binding energies with the water/butanol partition coeffcient did not lead to an improvement averaged over all receptor targets. Various consensus algorithms were investigated and a simple combination of AutoDock and AutoDock Vina results gave the most consistent performance that showed early enrichment of known ligands for all receptor targets investigated. In case a number ligands is known for a specific target, every method proposed in this study should be evaluated.

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“…Protein tyrosine phosphatase 1B (PTP1B) which was the first identified mammalian protein tyrosine phosphatase and key negative regulator of insulin signaling emerged as an attractive target for therapeutic intervention of type II diabetes [24]. Thus, PTP1B has attracted much attention in recent years due to its potential of treating diabetes and obesity [25][26]. In this study, the essential oils which have the PTP1B inhibitory activity were found.…”

Section: Introductionmentioning

confidence: 91%

Chemical components and antidiabetic activity of essential oils obtained by hydrodistillation and three solvent extraction methods fromCarthamus tinctoriusL.

Li¹,

Wang²,

Yang³

et al. 2012

Acta Chromatographica

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Summary. The chemical compositions of essential oils extracted by n-hexane extract (HE), petroleum ether extract (PE), dichloromethane extract (DE), and hydrodistillation (HD) from Carthamus tinctorius L. (safflower) were analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 86 compounds from four different extracts were identified, and the contents were 97.65%, 98.05%, 98.93%, and 99.68%, respectively. 6,10,14-Trimethyl-2-pentadecanone, hexadecanoic acid, methyl ester, hexadecanoic acid, 8,11-octadecadienoic acid, methyl ester, and 9,12,15-octadecatrien-1-ol were the major constituents of the extracts. The antidiabete activity was assayed in vitro by against protein tyrosine phosphatase 1B (PTP1B). The results showed that the HE exhibited the best in vitro inhibitory enzyme activity against PTP1B, which holds a good potential for treating diabetes and obesity.

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Structure-based virtual screening approach to identify novel classes of PTP1B inhibitors

Cited by 37 publications

References 25 publications

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity

Consensus virtual screening approaches to predict protein ligands

Chemical components and antidiabetic activity of essential oils obtained by hydrodistillation and three solvent extraction methods fromCarthamus tinctoriusL.

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