In silico pharmacology suggests ginger extracts may reduce stroke risks

Chang, Tung Ti; Chen, Kuan‐Chung; Chang, Kai Wei; Chen, Hsin Yi; Tsai, Fuu Jen; Sun, Mao; Chen, Calvin Yu-Chian

doi:10.1039/c1mb05228d

Cited by 46 publications

(32 citation statements)

References 29 publications

(15 reference statements)

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“…For example, the multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrug resistance (MDR) in about half of human cancers. P-gp encoded by a single gene in the human MDR1 gene is a member of the ATP binding cassette (ABC) family (Cascorbi et al, 2001;Chang et al, 2011a;Chen & Chen, 2010;Dean, Hamon, & Chimini, 2001;Sharom, 2008;Stefkova, Poledne, & Hubacek, 2004), which contributes to MDR in numerous types of human cancers and infectious diseases (Chang et al, 2011b(Chang et al, , 2011c(Chang et al, , 2011dChen, 2009Chen, , 2010Gottesman, Pastan, & Ambudkar, 1996;Wind & Holen, 2011). ABC importers and exporters are very important for their clinical relevance (Gottesman & Ling, 2006).…”

Section: Introductionmentioning

confidence: 99%

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

Liu¹,

Hou²,

Feng³

et al. 2013

Journal of Biomolecular Structure and Dynamics

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The multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrug resistance in about half of human cancers. Recently, high resolution X-ray crystal structures of mouse P-gp (inward-facing) were reported, which significantly facilitates the understanding of the function of P-gp and the structure-based design of inhibitors for P-gp. Here we perform 20 ns molecular dynamics simulations of inward-facing P-gp with/without ligand in explicit lipid and water to investigate the flexibility of P-gp for its poly-specific drug binding. By analyzing the interactions between P-gp and QZ59-RRR or QZ59-SSS, we summarize the important residues and the flexibility of different parts of P-gp. Particularly, the flexibility of the side chains of aromatic residues (Phe and Tyr) allows them to form rotamers with different orientations in the binding pocket, which plays a critical role for the poly-specificity of the drug-binding cavity of P-gp. MD simulations reveal that trans-membrane (TM) TM12 and TM6 are flexible and contribute to the poly-specific drug binding, while TM4 and TM5 are rigid and stabilize the whole structure. We also construct outward-facing P-gp based on the MsbA structure and perform 20 ns MD simulations. The comparison between the MD results for outward-facing P-gp and those for inward-facing P-gp shows that the TM parts in outward-facing P-gp undergo significant conformational change to facilitate the export of small molecules.

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Section: Introductionmentioning

confidence: 99%

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

Liu¹,

Hou²,

Feng³

et al. 2013

Journal of Biomolecular Structure and Dynamics

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“…In their pursuit of finding PDE4D inhibitors they screened compounds from TCM database followed by modelling techniques, molecular dynamics simulation and HypoGen validation. They also characterized the ligand binding properties that were associated with inhibition of PDE4D [52]. associate it as a risk factor for stroke among different ethnicities.…”

Section: Pharmacology Studiesmentioning

confidence: 98%

“…The carboxyl group and hydrophobic regions were identified as the potent dual targets that inhibit PDE4D and ALOX5AP activities [51]. Another study by Chang et al (2011) suggested that 3 compounds from ginger family were capable in inhibiting cAMP-binding and hydrolysis by PDE4D. In their pursuit of finding PDE4D inhibitors they screened compounds from TCM database followed by modelling techniques, molecular dynamics simulation and HypoGen validation.…”

Section: Pharmacology Studiesmentioning

confidence: 98%

Association between PDE4D gene and ischemic stroke: recent advancements

Das

Roy

Munshi

2015

International Journal of Neuroscience

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Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.

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“…In previous researches, it was proven that many compounds extracted from traditional Chinese medicine (TCM) can be recognized as potential lead compounds treated for viral infection [25–28], stroke prevention [29–31], cancers [32–35], and metabolic syndrome [36–38]. To improve drug development from TCM compounds, this study employed the compounds from TCM Database@Taiwan for virtual screening to identify the potential PARP-1 inhibitors from the vast repertoire of TCM compounds.…”

Section: Introductionmentioning

confidence: 99%

In Silico Investigation of Potential PARP‐1 Inhibitors from Traditional Chinese Medicine

Chen

Sun

Chen

2014

Evidence-Based Complementary and Alternative Medicine

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Poly(ADP-ribose) polymerases (PARPs) are nuclear enzymes which catalyze the poly-ADP-ribosylation involved in gene transcription, DNA damage repair, and cell-death signaling. As PARP-1 protein contains a DNA-binding domain, which can bind to DNA strand breaks and repair the damaged DNA over a low basal level, the inhibitors of poly(ADP-ribose) polymerase 1 (PARP-1) have been indicated as the agents treated for cancer. This study employed the compounds from TCM Database@Taiwan to identify the potential PARP-1 inhibitors from the vast repertoire of TCM compounds. The binding affinities of the potential TCM compounds were also predicted utilized several distinct scoring functions. Molecular dynamics simulations were performed to optimize the result of docking simulation and analyze the stability of interactions between protein and ligand. The top TCM candidates, isopraeroside IV, picrasidine M, and aurantiamide acetate, had higher potent binding affinities than control, A927929. They have stable H-bonds with residues Gly202 and, Ser243 as A927929 and stable H-bonds with residues Asp105, Tyr228, and His248 in the other side of the binding domain, which may strengthen and stabilize ligand inside the binding domain of PARP-1 protein. Hence, we propose isopraeroside IV and aurantiamide acetate as potential lead compounds for further study in drug development process with the PARP-1 protein.

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In silico pharmacology suggests ginger extracts may reduce stroke risks

Cited by 46 publications

References 29 publications

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

Association between PDE4D gene and ischemic stroke: recent advancements

In Silico Investigation of Potential PARP‐1 Inhibitors from Traditional Chinese Medicine

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