Bioinformatics and Molecular Design Research Center

Seoul, South Korea

Bioinformatics and Molecular Design Research Center

Seoul, South Korea
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Kim J.-H.,Yonsei University | Lim J.W.,Research and Development Center | Lim J.W.,Sejong University | Lee S.-W.,Research and Development Center | And 3 more authors.
Journal of Molecular Modeling | Year: 2011

Chemokine receptor 2 (CCR2) is a G-protein coupled receptor (GPCR) and a crucial target for various inflammatory and autoimmune diseases. The structure based antagonists design for many GPCRs, including CCR2, is restricted by the lack of an experimental three dimensional structure. Homology modeling is widely used for the study of GPCR-ligand binding. Since there is substantial diversity for the ligand binding pocket and binding modes among GPCRs, the receptor-ligand binding mode predictions should be derived from homology modeling with supported ligand information. Thus, we modeled the binding of our proprietary CCR2 antagonist using ligand supported homology modeling followed by consensus scoring the docking evaluation based on all modeled binding sites. The protein-ligand model was then validated by visual inspection of receptor-ligand interaction for consistency of published site-directed mutagenesis data and virtual screening a decoy compound database. This model was able to successfully identify active compounds within the decoy database. Finally, additional hit compounds were identified through a docking-based virtual screening of a commercial database, followed by a biological assay to validate CCR2 inhibitory activity. Thus, this procedure can be employed to screen a large database of compounds to identify new CCR2 antagonists. © 2011 Springer-Verlag.

In Y.,Bioinformatics and Molecular Design Research Center | Lee S.K.,Hannam University | Kim P.J.,National Institute of Environmental Research | No K.T.,Bioinformatics and Molecular Design Research Center | No K.T.,Yonsei University
Bulletin of the Korean Chemical Society | Year: 2012

We applied several machine learning methods for developing QSAR models for prediction of acute toxicity to fathead minnow. The multiple linear regression (MLR) and artificial neural network (ANN) method were applied to predict 96 h LC 50 (median lethal concentration) of 555 chemical compounds. Molecular descriptors based on 2D chemical structure were calculated by PreADMET program. The recursive partitioning (RP) model was used for grouping of mode of actions as reactive or narcosis, followed by MLR method of chemicals within the same mode of action. The MLR, ANN, and two RP-MLR models possessed correlation coefficients (R 2) as 0.553, 0.618, 0.632, and 0.605 on test set, respectively. The consensus model of ANN and two RP-MLR models was used as the best model on training set and showed good predictivity (R 2=0.663) on the test set.

Ye D.,CAS Shanghai Institute of Materia Medica | Shin W.-J.,Yonsei University | Li N.,CAS Shanghai Institute of Materia Medica | Tang W.,CAS Shanghai Institute of Materia Medica | And 11 more authors.
European Journal of Medicinal Chemistry | Year: 2012

With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents. © 2012 Elsevier Masson SAS. All rights reserved.

Lee S.,Yonsei University | Cho K.-H.,Soongsil University | Acree W.E.,University of North Texas | No K.T.,Yonsei University | No K.T.,Bioinformatics and Molecular Design Research Center
Journal of Chemical Information and Modeling | Year: 2012

We developed surface grid-based solvation free energy density (Surface-SFED) models for 36 commonly used polar solvents. The parametrization was performed with a large and diverse set of experimental solvation free energies mainly consisting of combinations of polar solvent and multipolar solute. Therefore, the contribution of hydrogen bonds was dominant in the model. In order to increase the accuracy of the model, an elaborate version of a previous hydrogen bond acidity and basicity prediction model was introduced. We present two parametrizations for use with experimentally determined (Surface-SFED/HB exp) and empirical (Surface-SFED/HB cal) hydrogen bond acidity and basicity values. Our computational results agreed well with experimental results, and inaccuracy of empirical hydrogen bond acidity and basicity values was the main source of error in Surface-SFED/HB cal. The mean absolute errors of Surface-SFED/HB exp and Surface-SFED/HB cal were 0.49 and 0.54 kcal/mol, respectively. © 2012 American Chemical Society.

Yim W.C.,Dongguk University | Keum C.,Bioinformatics and Molecular Design Research Center | Kim S.,Macrogen | Cho Y.,Dongguk University | And 2 more authors.
Toxicology and Environmental Health Sciences | Year: 2010

17β-estradiol (E2) is an environmental estrogen-like chemicals that is known to affect mainly reproductive functions of exposed targets. Although microarray based toxicogenomics approach allows the investigation of the potential risks of E2 in DNA level, the underling mechanisms related to their toxic effect is not fully understood. In this work, we identified genes responding toE2 by analyzing cross-experiment public gene expression datasets that studied on E2 using RankProd algorithm. We have identified 348 DEGs which play important roles in fatty acid metabolism, infection, and DNA repair. This result was also compared with conventional PubMed data mining analysis. © 2010 The Korean Society of Environmental Risk Assessment and Health Science and Springer.

Shim H.J.,Yonsei University | Yang H.R.,Sungkyunkwan University | Kim H.I.,Yonsei University | Kim H.I.,Shingyeong University | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

A lead compound 1, which inhibits the catalytic activity of PTK6, was selected from a chemical library. Derivatives of compound 1 were synthesized and analyzed for inhibitory activity against PTK6 in vitro and at the cellular level. Selected compounds were analyzed for cytotoxicity in human foreskin fibroblasts using MTT assays and for selectivity towards PTK members in HEK 293 cells. Compounds 20 (in vitro IC50= 0.12 μM) and 21 (in vitro IC50= 0.52 μM) showed little cytotoxicity, excellent inhibition of PTK6 in vitro and at the cellular level, and selectivity for PTK6. Compounds 20 and 21 inhibited phosphorylation of specific PTK6 substrates in HEK293 cells. Thus, we have identified novel PTK6 inhibitors that may be used as treatments for PTK6-positive carcinomas, including breast cancer. © 2014 Elsevier Ltd. All rights reserved.

Lee E.,Konkuk University | Jeong K.-W.,Konkuk University | Shin A.,Konkuk University | Jin B.,Konkuk University | And 5 more authors.
BMB Reports | Year: 2013

The anti-inflammatory activity of eriodictyol and its mode of action were investigated. Eriodictyol suppressed tumor necrosis factor (mTNF)-α, inducible nitric oxide synthase (miNOS), interleukin (mIL)-6, macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine release in LPS-stimulated macrophages. We found that the anti-inflammatory cascade of eriodictyol is mediated through the Toll-like Receptor (TLR)4/CD14, p38 mitogen-activated protein kinases (MAPK), extracellular-signalregulated kinase (ERK), Jun-N terminal kinase (JNK), and cyclooxygenase (COX)-2 pathway. Fluorescence quenching and saturation-transfer difference (STD) NMR experiments showed that eriodictyol exhibits good binding affinity to JNK, 8.79 × 105 M-1. Based on a docking study, we propose a model of eriodictyol and JNK binding, in which eriodictyol forms 3 hydrogen bonds with the side chains of Lys55, Met111, and Asp169 in JNK, and in which the hydroxyl groups of the B ring play key roles in binding interactions with JNK. Therefore, eriodictyol may be a potent anti-inflammatory inhibitor of JNK. © 2013 by the The Korean Society for Biochemistry and Molecular Biology.

PubMed | Yonsei University, Bioinformatics and Molecular Design Research Center and Korea Research Institute of Chemical Technology
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2016

The Dishevelled (Dvl) protein, which conveys signals from receptors to the downstream effectors, is a critical constituent of the Wnt/-catenin signaling pathway. Because the PDZ domain of Dvl protein functions through associations with a wide range of protein partners, Dvl protein involved in the Wnt signaling pathway has been considered to be therapeutic targets in cancers. In this study, we performed structure-based pharmacophore model of the Dvl PDZ domain to discover novel small-molecule binders and identified eight compounds with micromolar affinity. The most potent compound identified, BMD4702, efficiently bound to the Dvl PDZ domain with 11.2M affinity and had a 0.186M KD value according to surface plasmon resonance and fluorescence spectroscopy, respectively. Combining both structural-kinetic relationship analyses and docking studies, we fourmulated that the ligand-binding site is composed of three H-bonds and three hydrophobic features. Thus, our approach led to the identification of potent binders of the Dvl PDZ domain and the findings provide novel insights into structure-based approaches to design high-affinity binders for the Dvl PDZ domain.

Lee S.,Yonsei University | Cho K.-H.,Soongsil University | Lee C.J.,Yonsei University | Kim G.E.,Yonsei University | And 4 more authors.
Journal of Chemical Information and Modeling | Year: 2011

The solvation free energy density (SFED) model was modified to extend its applicability and predictability. The parametrization process was performed with a large, diverse set of solvation free energies that included highly polar and ionic molecules. The mean absolute error for 1200 solvation free energies of the 379 neutral molecules in 9 organic solvents and water was 0.40 kcal/mol, and for 90 hydration free energies of ions was 1.7 kcal/mol. Overall, the calculated solvation free energies of a wide range of solute functional groups in diverse solvents were consistent with experimental data. © 2011 American Chemical Society.

PubMed | Bioinformatics and Molecular Design Research Center
Type: Journal Article | Journal: Applied biochemistry and biotechnology | Year: 2014

Melanocytes are unique cells that produce specific melanin-containing intracellular organelles called melanosomes. Melanosomes are transported from the perinuclear area of melanocytes toward the plasma membrane as they become more melanized in order to increase skin pigmentation. In this vesicular trafficking of melanosomes, Rab27a, melanophilin, and myosin Va play crucial roles in linking melanosomes to actin-based motors. To identify novel compounds to inhibit binding interface between Rab27a and melanophilin, a pharmacophore model was built based on a modeled 3D structure of the protein complex that describes the essential binding residues in the intermolecular interaction. A pharmacophore model was employed to screen a chemical library database. Finally, 25 virtual hits were selected for biological evaluations. The biological activities of 11 analogues were evaluated in a second assay. Two compounds were identified as having concentration-dependent inhibitory activity. By analyzing structure-activity relationships of derivatives of BMD-20, two hydroxyl functional groups were found to be critical for blocking the intermolecular binding between Rab27a and melanophilin.

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