A possible strategy against head and neck cancer: in silico investigation of three-in-one inhibitors

Evidence-Based Complementary and Alternative Medicine

2014

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The peroxisome proliferator-activated receptors (PPARs) related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γ is the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM) using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD) simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γ protein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γ protein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs), the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γ protein.

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Potent PPAR‐γ Agonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

Evidence-Based Complementary and Alternative Medicine

2014

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“…According to these mechanisms, the researchers can identify the potential target protein for drug design against each disease [19–22]. The compounds extracted from traditional Chinese medicine (TCM) have been indicated in many in silico researches as potential lead compounds for the treatment of many different diseases, including tumours [23–26], diabetes [27], inflammation [28], influenza [29], metabolic syndrome [30], stroke [31–33], viral infection [34], and some other diseases [35, 36]. In this study, we aim to improve drug development of TCM compounds by investigating the potent lead compounds as PP2A agent from the TCM compounds in TCM Database@Taiwan [37].…”

Section: Introductionmentioning

confidence: 99%

Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer

Evidence-Based Complementary and Alternative Medicine

2014

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Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A-α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A-α protein.

“…Many compounds extracted from traditional Chinese medicine (TCM) had been determined as potential lead compounds for many different diseases, such as stroke [30–32], tumors [33–36], inflammation [37], metabolic syndrome [38–40], viral infection [41, 42], and some disorders [43–45]. As structural disordered amino acids in the binding domain of protein may affect the ligand binding with target protein and induce side effect [46, 47], the disordered amino acids of PXR protein were predicted before virtual screening.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Cardiovascular Disease by Traditional Chinese Medicine against Pregnane X Receptor

Chen¹,

BioMed Research International

Chen³

2014

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Recently, cardiovascular disease, also known as loop circulatory system diseases or disorders, is one of the serious diseases including heart disease, stroke, atherosclerosis, myocardial infarction, hypertension, hypotension, and thrombosis. Human pregnane X receptor, PXR, plays a crucial role in exogenous and endobiotic metabolism for rabbit, rat, mouse, and human. The PXR activation can protect the blood vessels from damage of hazardous substances. In this study we aim to investigate the potent lead compounds as PXR receptor agonist against cardiovascular disease. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as PXR agonists from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, bis(4-hydroxybenzyl) ether mono-β-D-glucopyranoside (BEMG), ixerisoside, and tangshenoside II, have displayed higher potent binding affinities than the positive control, PNU-142721, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and PXR protein under dynamic conditions, top TCM compounds, BEMG and tangshenoside II, maintain most of interactions with PXR protein, which keep the ligand binding stable in the binding domain. Hence, we propose BEMG and tangshenoside II as potential lead compounds for further study in drug development process with the PXR protein.