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

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.

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

BioMed Research International ◽

10.1155/2014/189495 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 1

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.

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

BioMed Research International ◽

10.1155/2014/429486 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 2

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.

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

BioMed Research International ◽

10.1155/2014/873010 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 1

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.

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

Coronaviruses ◽

10.2174/2666796702666210222105547 ◽

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.

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Inhibition of the mTORC2 and chaperone pathways to treat leukemia

Blood ◽

10.1182/blood-2011-12-399519 ◽

2012 ◽

Vol 119 (25) ◽

pp. 6080-6088 ◽

Cited By ~ 12

Author(s):

Fan Zhang ◽

Adam S. Lazorchak ◽

Dou Liu ◽

Fangping Chen ◽

Bing Su

Keyword(s):

Cell Growth ◽

Mammalian Target Of Rapamycin ◽

Leukemia Cell ◽

Mtor Inhibitors ◽

Hsp90 Inhibitor ◽

Human Leukemia ◽

Antitumor Effects ◽

Chaperone Protein ◽

The Stability

Abstract Constitutive activation of the kinases Akt or protein kinase C (PKC) in blood cancers promotes tumor-cell proliferation and survival and is associated with poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) regulates the stability of Akt and conventional PKC (cPKC; PKCα and PKCβ) proteins by phosphorylating the highly conserved turn motif of these proteins. In cells that lack mTORC2 function, the turn motif phosphorylation of Akt and cPKC is abolished and therefore Akt and cPKC protein stability is impaired. However, the chaperone protein HSP90 can stabilize Akt and cPKC, partially rescuing the expression of these proteins. In the present study, we investigated the antitumor effects of inhibiting mTORC2 plus HSP90 in mouse and human leukemia cell models and show that the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) preferentially inhibits Akt and cPKC expression and promotes cell death in mTORC2 deficient pre-B leukemia cells. Furthermore, we show that 17-AAG selectively inhibits mTORC2 deficient leukemia cell growth in vivo. Finally, we show that the mTOR inhibitors rapamycin and pp242 work together with 17-AAG to inhibit leukemia cell growth to a greater extent than either drug alone. These studies provide a mechanistic and clinical rationale to combine mTOR inhibitors with chaperone protein inhibitors to treat human blood cancers.

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Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis

BioMed Research International ◽

10.1155/2017/4751780 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Wei Wang ◽

Minghui Wan ◽

Dongjiang Liao ◽

Guilin Peng ◽

Xin Xu ◽

...

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Virtual Screening ◽

Md Simulation ◽

Interaction Analysis ◽

Docking Simulation ◽

Building Blocks ◽

Intracellular Channel

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

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Rapamycin-insensitive mTORC1 activity controls eIF4E:4E-BP1 binding

F1000Research ◽

10.12688/f1000research.1-4.v1 ◽

2012 ◽

Vol 1 ◽

pp. 4 ◽

Cited By ~ 26

Author(s):

Mark Livingstone ◽

Michael Bidinosti

Keyword(s):

Protein Complexes ◽

Mammalian Target Of Rapamycin ◽

Phosphorylation Site ◽

Mtor Inhibitors ◽

Kinase Domain ◽

Genetic Dissection ◽

Post Translational Modification ◽

Mtor Kinase ◽

Phosphorylation Event ◽

Mtor Protein

The recent development of mammalian target of rapamycin (mTOR) kinase domain inhibitors and genetic dissection of rapamycin-sensitive and -insensitive mTOR protein complexes (mTORC1 and mTORC2) have revealed that phosphorylation of the mTOR substrate 4E-BP1 on amino acids Thr37 and/or Thr46 represents a rapamycin-insensitive activity of mTORC1. Despite numerous previous reports utilizing serine (Ser)-to-alanine (Ala) and threonine (Thr)-to-Ala phosphorylation site mutants of 4E-BP1 to assess which post-translational modification(s) directly regulate binding to eIF4E, an ambiguous understanding persists. This manuscript demonstrates that the initial, rapamycin-insensitive phosphorylation event at Thr46 is sufficient to prevent eIF4E:4E-BP1 binding. This finding is relevant, particularly as mTOR kinase domain inhibitors continue to be assessed for clinical efficacy, since it clarifies a difference between the action of these second-generation mTOR inhibitors and those of rapamycin analogues.

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3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207320666170427143858 ◽

2017 ◽

Vol 20 (4) ◽

Cited By ~ 6

Author(s):

Jelena Oluić ◽

Katarina Nikolic ◽

Jelica Vucicevic ◽

Zarko Gagic ◽

Slavica Filipic ◽

...

Keyword(s):

Virtual Screening ◽

Antiproliferative Activity ◽

Mtor Inhibitors ◽

3D Qsar

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Design of potential IKK-β inhibitors using molecular docking and molecular dynamics techniques for their anti-cancer potential

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200102121505 ◽

2020 ◽

Vol 16 ◽

Author(s):

Salam Pradeep Singh ◽

Iftikar Hussain ◽

Bolin Kumar Konwar ◽

Ramesh Chandra Deka ◽

Chingakham Brajakishor Singh

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Md Simulation ◽

Inflammatory Diseases ◽

Binding Free Energy ◽

Anti Cancer ◽

Dietary Phytochemicals ◽

Toxicity Analysis ◽

The Stability ◽

Stable Trajectory

Aim and Objective: To evaluate a set of seventy phytochemicals for their potential ability to bind the inhibitor of nuclear factor kappaB kinase beta (IKK-β) which is a prime target for cancer and inflammatory diseases. Materials and Methods: Seventy phytochemicals were screened against IKK-β enzyme using DFT-based molecular docking technique and the top docking hits were carried forward for molecular dynamics (MD) simulation protocols. The adme-toxicity analysis was also carried out for the top docking hits. Results: Sesamin, matairesinol and resveratrol were found to be the top docking hits with a total score of -413 kJ/mol, -398.11 kJ/mol and 266.73 kJ/mol respectively. Glu100 and Gly102 were found to be the most common interacting residues. The result from MD simulation observed a stable trajectory with a binding free energy of -107.62 kJ/mol for matairesinol, -120.37 kJ/mol for sesamin and -40.56 kJ/mol for resveratrol. The DFT calculation revealed the stability of the compounds. The ADME-Toxicity prediction observed that these compounds fall within the permissible area of Boiled-Egg and it does not violate any rule for pharmacological criteria, drug-likeness etc. Conclusion: The study interprets that dietary phytochemicals are potent inhibitors of IKK-β enzyme with favourable binding affinity and less toxic effects. In fact, there is a gradual rise in the use of plant-derived molecules because of its lesser side effects compared to chemotherapy. The study has also provided an insight by which the phytochemicals inhibited the IKK-β enzyme. The investigation would also provide in understanding the inhibitory mode of certain dietary phytochemicals in treating cancer.

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Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach

Molecules ◽

10.3390/molecules26154424 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4424

Author(s):

Uzma Arshad ◽

Sibtain Ahmed ◽

Nusrat Shafiq ◽

Zaheer Ahmad ◽

Aqsa Hassan ◽

...

Keyword(s):

Virtual Screening ◽

Catalytic Amount ◽

Pyrimidine Derivatives ◽

Qsar Studies ◽

Lead Compounds ◽

Biological Potential ◽

Anti Cancer ◽

Anti Oxidant ◽

Vitro Analysis

Objective: In this study, small molecules possessing tetrahydropyrimidine derivatives have been synthesized having halogenated benzyl derivatives and carboxylate linkage. As previously reported, FDA approved halogenated pyrimidine derivatives prompted us to synthesize novel compounds in order to evaluate their biological potential. Methodology: Eight pyrimidine derivatives have been synthesized from ethyl acetoacetate, secondary amine, aromatic benzaldehyde by adding catalytic amount of CuCl2·2H2O via solvent less Grindstone multicomponent reagent method. Molecular structure reactivity and virtual screening were performed to check their biological efficacy as an anti-oxidant, anti-cancer and anti-diabetic agent. These studies were supported by in vitro analysis and QSAR studies. Results: After combined experimental and virtual screening 5c, 5g and 5e could serve as lead compounds, having low IC50 and high binding affinity.

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