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 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 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 Potential Mitochondrial Isocitrate Dehydrogenase R140Q Mutant Inhibitor from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Wen-Yuan Lee ◽  
Kuan-Chung Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Point Mutations ◽  
Docking Simulation ◽  
Myelogenous Leukemia ◽  
Mutant Protein ◽  
Binding Affinities ◽  
Isocitrate Dehydrogenase 1 ◽  
Lead Compounds ◽  
Arginine Residues ◽  
Acute Myelogenous

A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1and2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted fromAbrus precatoriusL., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.

scholarly journals In SilicoInvestigation of Potential PARP-1 Inhibitors from Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Mao-Feng Sun ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Docking Simulation ◽  
Binding Domain ◽  
Scoring Functions ◽  
Binding Affinities ◽  
Damage Repair ◽  
Dna Strand ◽  
The Stability ◽  
Dynamics Simulations ◽  
Aurantiamide Acetate ◽  
Parp 1

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.

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.

scholarly journals Potential Retinoid X Receptor Agonists for Treating Alzheimer’s Disease from Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Yu-Cheng Liu ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipoic Acid ◽  
Neurodegenerative Disorder ◽  
Phenyl Group ◽  
Docking Simulation ◽  
Sulfanilic Acid ◽  
Binding Affinities ◽  
Hydroxide Group ◽  
Lead Compounds

Alzheimer’s disease is neurodegenerative disorder due to the accumulation of amyloid-βin the brain and causes dementia with ageing. Some researches indicate that the RXR agonist, Targretin, has also been used for treatment of Alzheimer’s disease in mouse models. We investigate the potent candidates as RXR agonists from the vast repertoire of TCM compounds in TCM Database@Taiwan. The potential TCM compounds,β-lipoic acid and sulfanilic acid, had higher potent binding affinities than both 9-cis-retinoic acid and Targretin in docking simulation and have stable H-bonds with residues Arg316 and some equivalent hydrophobic contacts with residues Ala272, Gln275, Leu309, Phe313, Val342, Ile345, and Cys432 as Targretin. The carboxyl or sulfonyl hydroxide group can form a H-bond with key residue Arg316 in the docking pose, and the phenyl group next to the carboxyl or sulfonyl hydroxide group can form aπinteraction with residue Phe313. Moreover,β-lipoic acid and sulfanilic acid have stable H-bonds with residue Gln275, Ser313, and residue Ala327, respectively, which may strengthen and stabilize TCM candidates inside the binding domain of RXR protein. Hence, we proposeβ-lipoic acid and sulfanilic acid as potential lead compounds for further study in drug development process with the RXR protein against Alzheimer’s disease.

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

2015 ◽  
Vol 23 (15) ◽  
pp. 4815-4823 ◽  
Author(s):  
Yu Zhang ◽  
Bin Liu ◽  
Xingyu Wu ◽  
Ridong Li ◽  
Xianling Ning ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Kinase M2 ◽  
Lead Compounds

scholarly journals Virtual Screening of FDA-Approved Drugs against LasR of Pseudomonas aeruginosa for Antibiofilm Potential

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3723
Author(s):  
Suhaib Sadiq ◽  
Nosheen Fatima Rana ◽  
Muhammad Ammar Zahid ◽  
Muhammad Kazim Zargaham ◽  
Tahreem Tanweer ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Virtual Screening ◽  
Binding Pocket ◽  
Multi Drug Resistance ◽  
Binding Affinities ◽  
Binding Modes ◽  
Gastrointestinal Infections ◽  
The Stability ◽  
Approved Drugs

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation.

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