scholarly journals In SilicoInvestigation of Potential TRAF6 Inhibitor from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Wen-Yuan Lee ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Bos Taurus ◽  
Dynamic Condition ◽  
Hypoxia Inducible Factor ◽  
Tumor Necrosis Factor Receptor ◽  
Docking Simulation ◽  
Target Protein ◽  
Lead Compounds ◽  
Hypoxia Inducible Factor 1 ◽  
The Stability

It has been indicated that tumor necrosis factor receptor-associated factor-6 (TRAF6) will upregulate the expression of hypoxia-inducible factor-1α(HIF-1α) and promote tumor angiogenesis. TRAF6 proteins can be treated as drug target proteins for a differentiation therapy against cancers. As structural disordered disposition in the protein may induce the side-effect and reduce the occupancy for ligand to bind with target protein, PONDR-Fit protocol was performed to predict the disordered disposition in TRAF6 protein before virtual screening. TCM compounds from the TCM Database@Taiwan were employed for virtual screening to identify potent compounds as lead compounds of TRAF6 inhibitor. After virtual screening, the MD simulation was performed to validate the stability of interactions between TRAF6 proteins and each ligand. The top TCM compounds, tryptophan, diiodotyrosine, and saussureamine C, extracted fromSaussurea lappaClarke,Bos taurus domesticusGmelin, andLycium chinenseMill., have higher binding affinities with target protein in docking simulation. However, the docking pose of TRAF6 protein with tryptophan is not stable under dynamic condition. For the other two TCM candidates, diiodotyrosine and saussureamine C maintain the similar docking poses under dynamic conditions. Hence, we propose the TCM compounds, diiodotyrosine and saussureamine C, as potential candidates as lead compounds for further study in drug development process with the TRAF6 protein against cancer.

scholarly journals In SilicoInvestigation of Potential Pyruvate Kinase M2 Regulators from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Kuen-Bao Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Drug Development ◽  
Pyruvate Kinase ◽  
Md Simulation ◽  
Docking Simulation ◽  
Target Protein ◽  
Binding Affinities ◽  
Pyruvate Kinase M2 ◽  
Lead Compounds ◽  
The Stability

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

scholarly journals In SilicoInvestigation of Potential mTOR Inhibitors from Traditional Chinese Medicine for Treatment of Leigh Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Wen-Yuan Lee ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Md Simulation ◽  
Mammalian Target Of Rapamycin ◽  
Docking Simulation ◽  
Leigh Syndrome ◽  
Mtor Inhibitors ◽  
Mitochondrial Disorders ◽  
Lead Compounds ◽  
Mtor Protein ◽  
The Stability

A recent research demonstrates that the inhibition of mammalian target of rapamycin (mTOR) improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 andπinteractions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted fromPicrasma quassioides(D. Don) Benn. andVitex negundoL. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.

scholarly journals Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 412 ◽  
Author(s):  
Andrea Angeli ◽  
Fabrizio Carta ◽  
Alessio Nocentini ◽  
Jean-Yves Winum ◽  
Raivis Zalubovskis ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Carbonic Anhydrase ◽  
Drug Targets ◽  
Ph Regulation ◽  
Hypoxia Inducible Factor ◽  
Lead Compounds ◽  
Hypoxia Inducible Factor 1 ◽  
Ca Ix ◽  
Activation Of Transcription ◽  
Hif Pathway

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

scholarly journals Potential Smoothened Inhibitor from Traditional Chinese Medicine against the Disease of Diabetes, Obesity, and Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Mao-Feng Sun ◽  
Hsin-Yi Chen ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Drug Development ◽  
Hedgehog Signaling ◽  
Docking Simulation ◽  
Md Simulations ◽  
Positive Control ◽  
Lead Compounds ◽  
Oncology Clinical Trials ◽  
Body Patterning ◽  
The Stability ◽  
Smo Inhibitor

Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, 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 Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

scholarly journals Hypoxia-Inducible Factor-1 Expression Predicts Osteosarcoma Patients’ Survival: A Meta-Analysis

2016 ◽  
Vol 31 (3) ◽  
pp. 229-234 ◽  
Author(s):  
Yurong Ouyang ◽  
Hui Li ◽  
Jie Bu ◽  
Xiaoyang Li ◽  
Zhuoyuan Chen ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Hypoxia Inducible Factor ◽  
Disease Free Survival ◽  
Free Survival ◽  
Hypoxia Inducible Factor 1 ◽  
Proliferation And Metastasis ◽  
Primary Bone ◽  
The Stability ◽  
High Level

Osteosarcoma, the most common primary bone malignancy, is characterized by easily relapsing and metastasizing. Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumorigenesis, affecting tumor metabolism, differentiation, angiogenesis, proliferation and metastasis, and has been found to be associated with survival in patients with osteosarcoma. The possible prognostic value of HIF-1 was investigated in many studies, but the results were inconsistent. We therefore conducted a meta-analysis to elucidate the correlation of HIF-1 expression, analyzed by immunohistochemistry in osteosarcoma tissues, with prognosis. The association degree was assessed by calculation of the hazard ratio (HR) and risk ratio (RR) with corresponding 95% confidence intervals (CIs). Follow-up information was available for 486 patients from 7 studies. The results showed that high HIF-1 expression was associated with a worse prognosis when compared to low or undetectable HIF-1 expression, with an HR of 3.67 (95% CI 2.24-5.99; p<0.001) for overall survival (OS) and an RR of 3.72 (95% CI 2.26-6.13; p<0.001) for OS. The RR of 2.55 for disease-free survival (DFS) did not show any obvious relationship between a high level of HIF-1 and DFS (95% CI 0.95-6.87; p = 0.064). The stability of this result was tested by sensitivity analysis and no significant change was detected. This meta-analysis suggests that HIF-1 is an effective prognostic biomarker to predict OS in patients with osteosarcoma.

scholarly journals Autonomous molecule generation using reinforcement learning and docking to develop potential novel inhibitors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Woosung Jeon ◽  
Dongsup Kim
Keyword(s):  
Reinforcement Learning ◽  
Protein Structure ◽  
Virtual Screening ◽  
Computational Method ◽  
Target Protein ◽  
Training Data ◽  
Compound Library ◽  
Lead Compounds ◽  
Large Compound ◽  
Discoidin Domain Receptor 1

AbstractWe developed a computational method named Molecule Optimization by Reinforcement Learning and Docking (MORLD) that automatically generates and optimizes lead compounds by combining reinforcement learning and docking to develop predicted novel inhibitors. This model requires only a target protein structure and directly modifies ligand structures to obtain higher predicted binding affinity for the target protein without any other training data. Using MORLD, we were able to generate potential novel inhibitors against discoidin domain receptor 1 kinase (DDR1) in less than 2 days on a moderate computer. We also demonstrated MORLD’s ability to generate predicted novel agonists for the D4 dopamine receptor (D4DR) from scratch without virtual screening on an ultra large compound library. The free web server is available at http://morld.kaist.ac.kr.

Virtual Screening of the Flavonoids Compounds with the SARS-CoV-2 3C-like Protease as the Lead Compounds for the COVID-19

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Gabriella Patricia Adisurja ◽  
Arli Aditya Parkesit
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Specific Binding ◽  
Docking Simulation ◽  
Screening Methods ◽  
Lead Compound ◽  
Qsar Analysis ◽  
Lead Compounds ◽  
Protease Enzyme ◽  
Lead Source

: As per the1st of September 2020, the COVID-19 pandemic has reached an unprecedented level of more than 25 million cases with more than 850,000 deaths. Moreover, all the drug candidates are still undergoing testing in clinical trial. In this regard, a breakthrough in drug design is necessary. One strategy to devise lead compounds is leveraging natural products as a lead source. Several companies and research institutes are currently developing anti-SARS-CoV-2 leads from natural products. Flavanoids are well known as a class of antiviral compounds library. The objective of this research is to employ virtual screening methods for obtaining the best lead compounds from the library of flavonoid compounds. This research employed virtual screening methods that comprised of downloading the protein and lead compound structures, QSAR analysis prediction, iterations of molecular docking simulation, and ADME-TOX simulation for toxicity prediction. The QSAR analysis found that the tested compounds have broad-spectrum antiviral activity, and some of them exhibit specific binding to the 3C-like Protease of the Coronavirus. Moreover, juglanin was found as the compound with the most fit binding with the Protease enzyme of SARS-CoV-2. Although most of the tested compounds are deemed toxic by the ADME-Tox test, further research should be conducted to comprehend the most feasible strategy to deliver the drug to the infected lung cells. The juglanin compound is selected as the most fit candidate as the SARS-CoV-2 lead compound in the tested flavonoid samples. However, further research should be conducted to observe the lead delivery method to the cell.

Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Patients With Cancer ◽  
Hypoxia Inducible Factor 1 ◽  
Chemically Induced ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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