Chien Yu Chen

Ligand-Based Dual Target Drug Design for H1N1: Swine Flu- A Preliminary First Study

Abstract In March and April, 2009, an outbreak of H1N1 influenza in Mexico had led to hundreds of confirmed cases and the death toll had risen to 160. The worldwide spread of H1N1 has been attracting global attention and arising an overwhelming fear. So far, the vaccine and remedy has been in urgent need. In this study, a QSAR model and pharmacophore map of neuramini- dase (NA) type 1 (N1) contained two hydrogen bond acceptor features, one hydrogen bond donor feature, and one positive ionizable feature. NCI database was employed in virtual screen by the N1 pharmacophore map features. After screening, compounds were obtained and then docked into haemagglutinin type 1 (H1) to find out the candidate drugs for dual target of both N1 and H1. The candidate, NCI0353858, selected via virtual screening and docking, might be functional to this worldwide disease; consequently, further clinical investigations and scientific application are urgently demanded. We realize the proposed ligand does not have much validity without conducting a study on the stability of the protein-ligand complex by MD simulations and binding free energy, and such a study is underway and will be reported later in this journal. Nevertheless, the present study is clear, consistent and could give a rational explanation for the binding mode of the best selected ligand.

Structure-Based and Ligand-Based Drug Design for HER 2 Receptor

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.

Insights into designing the dual-targeted HER2/HSP90 inhibitors.

Heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are two key cancer markers actively involved in several signal pathways for cancer cell growth. In this study, we focused on the designing of dual-targeted HSP and HER2 inhibitors. Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and pharmacophore analysis were employed for generating the activity prediction models. The results of CoMFA model showed highly predictive r(2) value with 0.922 and 0.885 in HSP90 and HER2, respectively. In CoMSIA model, the r(2) values were 0.967 and 0.936 in HSP90 and HER2, respectively. The contour maps of both targets showed that there were similar regions of bulky favored area. Additionally, the Hypogen results for HER2 showed high cost difference as 59.13 and r-value as 0.909. At the C2 position of the benzene ring, the HER2 model favored steric bulkier substitutes more than HSP90. The Hypogen results for HSP90 also showed reliable values in cost difference, 85.82 and r-value, 0.902. Overall, we investigated the significances of QSAR models and pharmacophore features for designing the HER2/HSP90 dual-targeted inhibitors.

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis.

AbstractAim:To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum.Methods: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.Results: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.Conclusion: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.

Fabrication of SiO2@Au Core-Shell Multi-Functional Nanoparticles (MFNPs) for Imaging and Thermotherapy

In this study, we aimed at producing a MFNP consist of a dielectric core encapsulated fluorescein coating by a thin gold shell, which facilitate it with highly favorable optical and chemical properties for biomedical imaging and therapeutic applications. We have composed a novel multi-functional nanodesign, Sample A3, with fluorescein encapsulated in SiO2 nanoparticles with gold shell. The A3 nanoparticles were uniform in size, no aggregation, homogeneous and stable in the solution under the SEM image system. We have also investigated its cytotoxicity to A10 human smooth muscle cell line by MTT assay, and found that the novel sample A3 were of little cytotoxic to the cells. In conclusion, we have proposed a novel method of preparing multi-functional nanoparticles assemblies, which has added fluorescein to SiO2 in a gold shell, to make it simultaneously have the functions of photothermal therapy and tracer.

Study of AMP-Activated Protein Kinase Agonists by Structure-Based Drug Designing

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.

Drug Design for KU86 in DNA Break Repair System

XRCC4 was well known as the downstream of KU86DNA complex. They both play an important role in the DNA double-strain breaks (DSBs) repair system subpathway, nonhomologous end joining (NHEJ).In this study, The protocol of docking analysis was applied to find the specific compounds, which had highest affinities to KU86 from our TCM database. The docking results were analyzed to point out potent compounds. Xanthone-9, xanthone-11, 12, and Cycloheterophyllin were suggested as leading compounds for drug design by hydrogen bonds forming on Arg403 in Ku70 and Arg400 in Ku80 Then, xanthone-11 was selected to the protocol of de novo evolution. The diversities of xanthone-11 had 10 kinds of the result of de novo evolution. We suggested that the diversities could be the potent compounds of inhibitors for KU86. KeywordsKU86; traditional Chinese medicine (TCM); DNA double-strand breaks (DSBs)

Is that Possible to Design the Versatile Inhibitors for H1N1, H5N1, H5N2, and H5N7?

In this study, a QSAR model of neuraminidase (NA) type 1 (N1) 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 N1, N2, and N7 had subtle differences in distances of each features. We created the combined map for N1, 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.

Drug Design for the Influenza A Virus Subtype H1N1

In March and April 2009, an outbreak of H1N1 influenza in Mexico led to hundreds of confirmed cases and a number of deaths. The worldwide spread of H1N1 had attracted everyone’s attention and arisen an overwhelm fear. Up to now, there is still an urgent need in the solution for ending this fight. In this study, a QSAR model of neuraminidase (NA) type 1 (N1) provides an access. The pharmacophore map of N1 contained two hydrogen bond acceptor features, one hydrogen bond donor features, and one positive ionizable feature .NCI database was screened by this map to find potent inhibitors of N1. Then, those inhibitors were docked into hemagglutinin type 1 to find out the candidate drugs. The candidate drugs selected via computeraided drug designing program may be very useful in this worldwide disease, and further investigations in its clinical and scientific application are urgently needed. KeywordsH1N1; influenza; drug design; docking

What is the Key Point for Designing HER2 Inhibitors

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. KeywordsHER2; traditional Chinese medicine; pi-stacking