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ABSTRACT: Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inhibition or denaturation of IN is a possible method for inhibiting HIV replication. D77 is a known drug with demonstrated inhibition against HIV by binding to IN. Herein, we utilized D77 as a control to screen for traditional Chinese medicine (TCM) compounds that exhibit similar atomic-level characteristics. 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores to IN than D77 through virtual screening. Multiple linear regression (R2 = 0.9790) and support vector machine (R2 = 0.9114) models consistently predicted potential bioactivity of the TCM candidates against IN. The 40 ns molecular dynamics simulation showed that the TCM compounds fulfilled the drug-like criteria of forming stable complexes with IN. Atomic-level investigations revealed that 9-hydroxy-(10E)-octadecenoic acid bound to an important residue A:Lys173, and Beauveriolide I formed stable interactions with the core LEDGF binding site and with Asn256 of the IN binding site on LEDGF. The TCM candidates also initiated loss of α-helices that could affect the functionality of IN. Taken together, the ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to (1) form stable interactions affecting IN-LEDGF binding and (2) have predicted bioactivity against IN suggests that the TCM candidates might be potential starting structures for developing compounds that may disrupt IN-LEDGF binding. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:40.
Journal of biomolecular structure & dynamics 12/2012; · 4.99 Impact Factor
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ABSTRACT: Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.
Journal of biomolecular structure & dynamics 06/2012; 30(6):662-83. · 4.99 Impact Factor
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ABSTRACT: New-type oseltamivir-resistant H1N1 influenza viruses have been a major threat to human health since the 2009 flu pandemic. To resolve the drug resistance issue, we aimed to identify a new type of inhibitors against H1 from traditional Chinese medicine (TCM) by employing the world's largest TCM database () for virtual screening and molecular dynamics (MD). From the virtual screening results, sodium (+)-isolaricireinol-2 alpha-sulfate, sodium 3,4-dihydroxy-5-methoxybenzoic acid methyl ester-4-sulfate, sodium (E)-7-hydroxy-1,7-bis(4-hydroxyphenyl)hept-5-ene-3S-sulfonate, and 3-methoxytyramine-betaxanthin were identified as potential drug-like compounds. MD simulation of the binding poses with the key residues Asp103 and Glu83, as well as other binding site residues, identified higher numbers of hydrogen bonds than N-Acetyl-D-Glucosamine (NAG), the natural ligand of the esterase domain in H1. Ionic bonds, salt bridges, and electrostatic energy also contribute to binding stability. Key binding residues include Lys71, Glu83, Asp103, and Arg238. Structural moieties promoting H-bond or salt bridge formations at these locations greatly contribute to a stable ligand-protein complex. An available sodium atom for ionic interactions with Asp103 can further stabilize the ligands. Based on virtual screening, MD simulation, and interaction energy evaluation, TCM candidates demonstrate good potential as novel H1 inhibitors. In addition, the identified stabilizing features can provide insights for designing highly stable H1 inhibitors.
Molecular BioSystems 12/2011; 7(12):3366-74. · 3.53 Impact Factor
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ABSTRACT: The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.
PLoS Computational Biology 12/2011; 7(12):e1002315. · 5.22 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptors alpha, delta and gamma are a collection of ligand-activated transcription factors crucial in lipid and glucose homeostasis. The involvement of these receptors in lipid metabolism makes them perfect therapeutic target for treating obesity and stroke. In this study, 'sum of activity' model was employed to design multi-target agonists. We used a new strategy to design agonists that fit both alpha and delta but not gamma, to avoid side effect. The CoMFA and CoMSIA models were used to explore the pharmacophore features by constructing three individual models: (a) alpha-model, (b) delta-model and (c) gamma-model, and two sum models: (d) alpha, delta- model, and (e) alpha, delta and gamma-model. The CoMFA model yielded a significant cross validation value, q(2), of 0.729 and non-cross validation value, r(2), of 0.933 in the alpha, delta-model. The CoMSIA studies yielded the best predictive models with q(2) of 0.622 in A+S and with r(2) of 0.911 in the alpha, delta-model. Finally, we proposed that distinct features shown in models (a), (b), (d) but not (c) and (e) should be accounted in designing weight-controlling drugs.
Journal of biomolecular structure & dynamics 10/2010; 28(2):187-200. · 4.99 Impact Factor
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ABSTRACT: Human epidermal growth factor receptor 2, HER2, is a commonly over-expressed tyrosine kinase receptor found in many types of carcinoma. Despite that there are several HER2 inhibitors, namely Iressa, Tarceva and Tykerb, currently in clinical trials, all can cause several side effects. In this study, both structure-based and ligand-based drug design were employed to design novel HER2 inhibitors from traditional Chinese medicine (TCM). The HER2 structure model was built in homology modeling based on known receptors of the same family. Docking and de novo evolution experiments were performed to identify candidates and to build derivatives. A training set of 32 compounds with inhibitory activities to HER2 was used to formulate the pharmacophore hypotheses that were subsequently used to examine candidates obtained from the docking study. Hydrogen bond interactions, salt-bridge formations and pi-stacking were observed between the ligands and Phe731, Lys753, Asp863 and Asp808 of HER2 protein. Combining results from both docking and pharmacophore mapping analysis, CLC015-5, CLC604-11 and CLC604-18 were well accepted and consistent in both approaches and were considered as the most potential HER2 inhibitors.
Journal of biomolecular structure & dynamics 08/2010; 28(1):23-37. · 4.99 Impact Factor
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ABSTRACT: This study could show that the potent inhibitor of PDE5 from Epimedium sagittatum components. The PDE 5 inhibitors of data set from Xia's study were calculated their properties. Multiple linear regression analysis was used to build the QSAR model. Those properties were associated to drug activities by the QSAR model. This result showed high correlation (R2 = 0.848) with drug activities in this QSAR model. The weights of those properties were -5.359, 6.434, -3.959, 5.149, and 8.689. In the result of prediction, the correlation was employed to predict pIC50 of the ES series (Cialis = 7.988, ES02 = 6.31, ES03a = 9.78, ES03b = 10.03). The docking protocol was used to prove the trend of prediction. This result showed the same trend in docking scores (Cialis = 53.271, ES02 = 57.864, ES03a = 64.260, ES03b = 76.915). According to those results, ES03b was elevated to be a potent inhibitor of PDE5.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: AMP-activated protein kinase (AMPK) is a metabolite- sensed protein kinase in various eukaryotes. The activated AMPK regulates important proteins which cause diabetes, obesity, metabolic aberrant, and also breast cancer. In this study, the yeast AMPK structure was used as a template to model the human AMPK structure. By homology modeling, the reliable AMPK structure was built, and the active binding site was defined corresponding to X-ray crystal structure of yeast AMPK By virtual screening the database. All the potent ligands had the H-bond interaction in the key residues, same as the control. Thus, we suggested the phenylamide derivates might be the potent AMPK agonists.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: HER2 over-expression associates with many cancer symptoms, and the HER2 protein kinase was regarded as the target for cancer treatment. To develop the novel potent leads, homology modeling and structure-based design were employed to this research. Three clinical trail drugs and traditional Chinese medicine (TCM) database were employed to perform the docking. The top 7 compounds from database with higher DockScore were selected to develop 210 virtual compounds by De novo evolution, and the 210 derivative compounds were further conform the Lipinski's Rule (rule of five) to ensure the rational in real condition. In the docking result of serial selection, CLC0155, CLC015-11, CLC015-12, CLC604-11, and CLC604-18 presented the pi-stacking interaction and hydrogen bond interaction with the key residues, and had higher DockScore than clinical trail drugs and original compounds. These five selected compounds were suggested the potent ATP-binding inhibitors and might guide for further drug design.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: In this study, a QSAR model of neuraminidase (NA) type 1 (Nl) was elevated. This map contained two hydrogen bond acceptor features, one hydrogen bond donor features, and one positive ionizable feature. In the second step, we created the interaction maps in the active sites on the neuraminidase type2, and type7 (N2 and N7) protein structures. The structure-based pharmacophore map was showed the features on every amino acid in the active site on the protein structure. The third step was pharmacophore comparison, root-mean-squared error (RMSE) was reported for the matching pharmacophore features. The result showed that the maps of Nl, N2, and N7 had subtle differences in distances of each features. We created the combined map for Nl, N2, and N7 to resolving the difference in the three NA types. The combined map was employed to NCI database screening, then, the potent versatile inhibitors were elevated in the results.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: XRCC4-DNA ligase IV complex is critical in nonhomologous end-joining DNA repair system. Inhibition of its formation is potential in cancer cell killing, while no related study was reported. Herein, the structure-based drug design was used to develop potent compounds in this study. Firstly, the Traditional Chinese Medicine database was employed to dock into the binding site of XRCC4; then the top 10 output compounds were regarded as the scaffolds for further de novo evolution. Secondly, 99 diversities outcome were screened by Lipinski's Rule (rules of five) and the survivors were put into the second round of docking study. As a result, diversities with higher DockScore than the top 10 of DockScore from the first round were selected for pose analysis. Finally, 8 diversities were suggested to behave strongest inhibitory effects on XRCC4-DNA ligase IV complex formation. The 8 candidates selected by this study may serve as potent personalized anticancer drugs.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: In this investigation, the CoMFA and CoMSIA in the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were implemented to search for the pharmacophore features in each target receptor. QSAR pharmacophores hypothesis models were made from a series of ligands by their activity values. Besides, we made use of the docking strategy between the structures of each PPARs subtype. Eventually, selectivity factor is employed for us to search new drugs. By means of taking advantage of the results of 3D-QSAR studies and docking strategy, we search out the specific drugs fitting the two PPAR subtypes but repelling the other PPAR subtype effectively and selectively.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: Heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 protein (HER2) are involved in several signal pathways for cancer cell proliferation. We focused on these two hallmarkers to design the dual-targeted inhibitors for cancer therapy. The comparative molecular field analysis (CoMFA) and pharmacophore analysis were employed for generating the predictive models. According the leave-one out (LOO) cross-validation, the CoMFA models obtained the significant r2 values of 0.978 and 0.974 for HSP90 and HER2, respectively. The contour maps of both targets indicated that there were amount of similar bulky favors area. Besides, the cost difference of pharmacophore models was 48.539 for 70% correlation with the experiment. The queries at 3-N and 6-N position of purine-based compound had the similar distributions. This study provided important information for design the HER2 and HSP90 dual-targeted inhibitors.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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Chien-Yu Chen,
Fuu-Jen Tsai,
Jing-Gung Chung,
Chang-Hai Tsai,
Yuan-Man Hsu, Hung-Jin Huang,
Tin-Yun Ho,
Yea-Huey Chang,
Da-Tian Bau,
Ming-Hsui Tsai,
C.Y.-C. Chen
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ABSTRACT: This is the first time that we reported about dual target inhibitors of KU86 and XRCC4. XRCC4 was well known as the downstream of KU86-DNA complex. They both play an important role in the DNA double-strain breaks (DSBs) repair system subpathway, non-homologous end joining (NHEJ).In this study, The protocol of docking analysis was applied to find the specific compounds, which had highest affinities to KU86 and XRCC4, from our database. The docking results were analyzed by cross validation. From the results above, myricetin and xanthone series had quietly the same core structure. The different shapes of binding sites from the two proteins might be the major factor to different affinities from these three potent dual-target inhibitors. Our work provides a new strategy for developing dual-target anticancer drug, and may contribute to clinical anticancer drug discovery and application.
Biomedical Engineering and Informatics, 2009. BMEI '09. 2nd International Conference on; 11/2009
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ABSTRACT: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum.
We predicted the potent compound, ES03b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship (QSAR) model, which was constructed by multiple linear regression.
ES03b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. ES03b generated 49 diversities (Evo01-49). Evo48 had high activity in prediction. Although the value of prediction was overestimated, Evo48 was suggested as the potent lead.
In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.
Acta Pharmacologica Sinica 09/2009; 30(8):1186-94. · 1.95 Impact Factor
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ABSTRACT: Aim: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum.
Acta Pharmacologica Sinica 07/2009; 30(8):1186-1194. · 1.95 Impact Factor
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Proceedings of the 2nd International Conference on BioMedical Engineering and Informatics, BMEI 2009, October 17-19, 2009, Tianjin, China; 01/2009
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Proceedings of the 2nd International Conference on BioMedical Engineering and Informatics, BMEI 2009, October 17-19, 2009, Tianjin, China; 01/2009
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ABSTRACT: An outbreak of influenza A virus subtype H1N1, also known as swine flu, in Mexico was occurred in April 2009. To design drugs for treating this epidemic is urgency. In this study, we employed the new sequences (2009) to build the N1 simulation structure by homology modeling, which has been checked for high reliability by Verify Score and Ramachandran plot. The latest H1 homology model was employed from Chen's report. 365,602 compounds from NCI database have been screened by docking study of H1 and N1, respectively. And then, nine candidates were screened and suggested as potent dual target candidates from the docking studies. In our investigation, drug resistance was found by our molecular simulation in the new N1 modeling structure to oseltamivir. However, the mechanism is still not clear; further clinical investigations are urgently required.
Journal of the Taiwan Institute of Chemical Engineers.
