Hsin-Yi Chen

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.

A Novel Strategy for Designing the Selective PPAR Agonist by the “Sum of Activity” Model

Abstract Peroxisome proliferator-activated receptors α, δ, and γ 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 α and δ but not γ to avoid side effect. The CoMFA and CoMSIA models were used to explore the pharmacophore features by constructing three individual models: (a) α-model, (b) δ-model and (c) γ-model, and two sum models: (d) α, δ- model, and (e) α, δ, γ- model. The CoMFA model yielded a significant cross validation value, q2, of 0.729 and non-cross validation value, r2, of 0.933 in the alpha;, δ-model. The CoMSIA studies yielded the best predictive models with q2 of 0.622 in A + S and with r2 of 0.911 in the α, δ-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.

Investigation into Potent Inflammation Inhibitors from Traditional Chinese Medicine

Microsomal prostaglandin E synthase‐1 (mPGES‐1) is the key enzyme for prostaglandin E2 (PGE2) generation during inflammation and is a potential target for designing anti‐inflammatory drugs. Potential inhibitors of m‐PGES‐1 were selected from traditional Chinese medicine (TCM Database@Taiwan) based on the pharmacophore map generated by the top HypoGen hypothesis and validated using structure‐ and ligand‐based analysis. Key features for potential m‐PGES‐1 inhibitors include pi‐interactions and H‐bond donors. TCM compounds, shanciol B, shanciol A, castilliferol, and aurantiamide acetate, contoured to the quantitative structure–activity relationship pharmacophore and exhibited high docking scores and binding stability with m‐PGES‐1. Bioactivity models multiple linear regression (MLR) and support vector machine also supported activity predictions for the candidate compounds. Our results indicate that the investigated TCM compounds could be of use for development into mPGES‐1 inhibitors.

Screening from the world's largest tcm database against h1n1 virus

Abstract The swine influenza virus (H1N1) 2009 pandemic highlights the importance of having effective anti-viral strategies. Recently, oseltamivir (Tamiflu) resistant influenza viruses are identified; which further emphasizes the urgency in developing new antiviral agents. In influenza virus replication cycle, viral surface glycoprotein, hemagglutinin, is responsible for viral entry into host cells. Hence, a potentially effective antiviral strategy is to inhibit viral entry mechanism. To develop novel antiviral agent that inhibits viral entry, we analyzed 20,000 traditional Chinese medicine (TCM) ingredients in hemagglutinin subtype H1 sialic acid binding site found on H1N1 virus. We then performed molecular dynamics simulations to investigate receptor-ligand interaction of the candidates obtained from docking. Here, we report three TCM derivatives that have high binding affinities to H1 sialic acid binding site residues based on structure-based calculations. The top three derivatives, xylopine_2, rosmaricine_14 and rosmaricine_15, all have an amine group that interact with Glu83 and a pyridinium group that interact with Asp103. Molecular dynamics simulations show that these derivatives form strong hydrogen bonding with Glu83 but interact transiently with Asp103. We therefore suggest that an enhanced hemagglutinin inhibitor, based on our scaffold, should be designed to bind both Glu83 and Asp103 with high affinity.

iSMART: An Integrated Cloud Computing Web Server for Traditional Chinese Medicine for Online Virtual Screening, de novo Evolution and Drug Design

(2011). iSMART: An Integrated Cloud Computing Web Server for Traditional Chinese Medicine for Online Virtual Screening, de novo Evolution and Drug Design. Journal of Biomolecular Structure and Dynamics: Vol. 29, No. 1, pp. 243-250.

In silico pharmacology suggests ginger extracts may reduce stroke risks

Aberrations in cyclic adenosine monophosphate (cAMP) signaling cascade has been linked to the allergic responses that associate with the risks of stroke or cardiovascular diseases. Phosphodiesterase 4D (PDE4D) has been shown to be highly involved in cAMP regulation and is hence implied to be a potential drug target in stroke prevention. To identify potential PDE4D inhibitors from traditional Chinese medicine (TCM), we employed machine learning modeling techniques to screen a comprehensive TCM database. The multiple linear regression (MLR) and support vector machine (SVM) models constructed have correlation coefficients of 0.8234 and 0.7854 respectively. Three candidates from the ginger family were identified based on the prediction models. Molecular dynamics simulation further validated the binding stabilities of each candidate in comparison to the control inhibitor L-454560. The intermolecular distances suggested that the candidates could hinder PDE4D from binding to cAMP. Furthermore, the HypoGen validation suggested that top2, top3, and the control L-454560 mapped with the predicted pharmacophores. The results suggested that the 3 compounds identified from the ginger family were capable in inhibiting cAMP binding and hydrolysis by PDE4D. We further identified and characterized the ligand binding properties that are associated with the inhibition of PDE4D.

Potent Inhibitor Design Against H1N1 Swine Influenza: Structure-based and Molecular Dynamics Analysis for M2 Inhibitors from Traditional Chinese Medicine Database

Abstract The rapid spread of influenza virus subtype H1N1 poses a great threat to million lives worldwide. To search for new anti-influenza compounds, we performed molecular docking and molecular dynamics simulation to identify potential traditional Chinese medicine (TCM) constituents that could block influenza M2 channel activity. Quinic acid, genipin, syringic acid, cucurbitine, fagarine, and methyl isoferulate all have extremely well docking results as compared to control amantadine. Further de novo drug design suggests that derivatives of genipin and methyl isoferulate could have enhanced binding affinity towards M2 channel. Selected molecular dynamics simulations of M2-derivative complexes show stable hydrogen bond interactions between the derivatives and M2 residues, Ser10 and Ala9. To our best knowledge, this is the first study on the anti-viral activity of the above listed TCM compounds.

Ethambutol-induced optic neuropathy: a nationwide population-based study from Taiwan

Aim To investigate the risk factors and comorbidities associated with ethambutol-induced optic neuropathy (EON). Method Using the Taiwan Longitudinal Health Insurance Database, we conducted a study within a nationwide representative cohort of patients treated with EMB. We identified 231 patients newly diagnosed with EON between 2000 and 2008, and 924 control subjects. Adjusted OR by estimating the risk of EON in relation to comorbidities and EMB prescription protocol was determined. Results Compared with the control group, EON patients were at risk with older age, hypertension (adjusted OR=1.62, 95% CI 1.16 to 2.26) and renal diseases (without end-stage renal diseases (ESRD), adjusted OR=2.11, 95% CI 1.02 to 4.35; with ESRD, adjusted OR=3.73, 95% CI 1.79 to 7.74). Patients with an EMB prescription duration longer than 3 months were not at elevated risk compared with those whose prescription less than 3 months (OR=1.35, 95% CI 0.99 to 1.83, adjusted for age, sex, hypertension and renal diseases). Patients whose average daily dose was greater than 1200 mg, compared with the other two groups (800∼1199 mg, less than 800 mg) were not at increased risk for EON. Conclusions Age, hypertension and renal diseases are risk factors for EON in the Taiwanese population.

Key Features for Designing Phosphodiesterase-5 Inhibitors

Abstract Phosphodiesterase superfamily is the key regulator of 3′,5′-cyclic guanosine monophosphate (cGMP) decomposition in human body. Phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, vardenafil and tadalafil, are well known oral treatment for males with erectile dysfunction. To investigate the inhibitory effects of traditional Chinese medicine (TCM) compounds to PDE-5, we performed both ligand-based and structure-based studies on this topic. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted to construct three dimensional quantitative structure-activity relationship (3D-QSAR) models of series of known PDE-5 inhibitors. The predictive models had cross-validated, q2, and non cross-validated coefficient, r2, values of 0.791 and 0.948 for CoMFA and 0.724 and 0.908 for CoMSIA. These two 3D-QSAR models were used to predict activity of TCM compounds. Docking simulations were performed to further analyze the binding mode of training set and TCM compounds. A putative binding model was proposed based on CoMFA and CoMSIA contour maps and docking simulations; formation of pi-stacking, water bridge and specific hydrogen bonding were deemed important interactions between ligands and PDE-5. Of our TCM compounds, engeletin, satisfied our binding model, and hence, emerged as PDE-5 inhibitor candidate. Using this study as an example, we demonstrated that docking should be conducted for qualitative purposes, such as identifying protein characteristics, rather than for quantitative analyses that rank compound efficacy based on results of scoring functions. Prediction of compound activity should be reserved for QSAR analyses, and scoring functions and docking scores should be used for preliminary screening of TCM database (http://tcm.cmu.edu.tw/index.php).

Identification of melamine/cyanuric acid-containing nephrolithiasis by infrared spectroscopy.

Melamine‐contaminated milk formula caused infant nephrolithiasis in some areas of China. Its combination with cyanuric acid causes crystallization in renal tubules. Following this renal damage and even renal failure that require long‐term hemodialysis has been reported. Therefore, correct and timely diagnosis of these complex diseases is critical. Melamine containing stone is a combination of equal molar ratios of common stone compositions that has been reported from previous animal studies. We have previously identified the compositions of urinary tract stones with infrared (IR) spectroscopy. We hypothesized that the absorbance of wavelength of IR can identify melamine/cyanuric acid in the presence of mixing human stone compositions. In this study, we made an artificial stone composition and examine under IR absorbance by mixing equal molar ratios of melamine/cyanuric acid with different types of human urinary stones, and established a reference of IR analysis for the identification of melamine/cyanuric acid‐containing human urinary tract stones. Knowledge of the precise stone composition allowed institution of appropriate prophylactic dietary and medical therapy and this may help in the prevention of urinary stone recurrence. The results are promising that melamine and cyanuric acid can be identified clearly in a low percentile (∼1%) of stone mixture pellet. Therefore, IR seems to be an ideal tool for the identification of melamine/cyanuric acid‐containing stones. J. Clin. Lab. Anal. 24:92–99, 2010.