• Bulletin of the Korean Chemical Society
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• v.34 no.10
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• pp.2909-2914
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• 2013

p-Hydroxyphenylpyruvate dioxygenase (HPPD) is a potent herbicide target that is in current use. In this study, we developed a predictive pharmacophore model that uses known HPPD inhibitors based on a theoretically constructed HPPD homology model. The pharmacophore model derived from the three-dimensional (3D) structure of a target protein provides helpful information for analyzing protein-ligand interactions, leading to further improvement of the ligand binding affinity.

• Bulletin of the Korean Chemical Society
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• v.33 no.7
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• pp.2365-2368
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• 2012

The $11{\beta}$-hydroxysteroid dehydrogenase type 1 ($11{\beta}$-HSD1) enzyme is involved in modulation of glucocorticoid activity within target tissues. This enzyme may contribute to obesity and/or metabolic disease through its action in adipose or liver tissue. Inhibition of $11{\beta}$-HSD1 has major therapeutic potential for glucocorticoid-associated diseases, including obesity, diabetes (wound healing), and muscle atrophy. To develop such therapeutics, we performed a pharmacophore-based virtual screening (VS) for identification of novel $11{\beta}$-HSD1 inhibitors and found that the VS hit compounds show potent inhibition of $11{\beta}$-HSD1 enzyme activity. Further, we present a binding model for active compounds. The proposed pharmacophore may serve as a useful guideline for future design of new chemical entities as $11{\beta}$-HSD1-targeted antidiabetic agents.

• Bulletin of the Korean Chemical Society
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• v.31 no.7
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• pp.2039-2042
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• 2010

• Bulletin of the Korean Chemical Society
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• v.31 no.11
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• pp.3441-3444
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• 2010

• Bioinformatics and Biosystems
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• v.1 no.2
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• pp.115-122
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• 2006

A three-dimensional pharmacophore model was developed based on 24 currently available inhibitors, which were rationally selected from 472 compounds with diverse molecular structure and bioactivity, for generating pharmacophore of uPA (Urokinase Plasminogen Activator) inhibitors. The best hypothesis (Hypo1) comprised of five features, namely, one positive ionizable group, one hydrogen-bond acceptor group and three hydrophobic aromatic groups. The correlation coefficient, root mean square deviation and cost difference were 0.973, 0.695, and 94.291 respectively, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model showed great success in predicting the activities of 251 known uPA inhibitors (test set) with a correlation coefficient of 0.837, and there was also none of the outcome hypotheses that had similar cost difference and RMS deviation (RMSD) with that of the initial hypothesis generated by Cat-Scramble validation test with 95% confidence level. Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity.

• Bulletin of the Korean Chemical Society
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• v.34 no.7
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• pp.1972-1984
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• 2013

Microtubules play an important role in intracellular transport, mobility, and particularly mitosis. Paclitaxel (Taxol$^{TM}$) and paclitaxel-like compounds have been shown to be anti-tumor agents useful for various human tumors. Paclitaxel-like compounds operate by stabilizing microtubules through interface binding at the interface between two ${\beta}$-tubulin monomers in adjacent protofilaments. In this paper we present the elucidation of the structural features of paclitaxel and paclitaxel-like compounds (e.g., epothilones) with microtubule stabilizing activities, and relate their activities to spatial and chemical features of the molecules. CATALYST program was used to generate three-dimensional quantitative structure activity relationships (3D-QSARs) resulting in 3D pharmacophore models of epothilone- and paclitaxel-derivatives. Pharmacophore models were generated from diverse conformers of these compounds resulting in a high correlation between experimental and predicted biological activities (r = 0.83 and 0.91 for epothilone and paclitaxel derivatives, respectively). On the basis of biological activities of the training sets, five- and four-feature pharmacophore hypotheses were generated in the epothilone and paclitaxel series. The validation of generated hypotheses was achieved by using twelve epothilones and ten paclitaxels, respectively, which are not in the training sets. The clustering (grouping) and merging techniques were used in order to supplement spatial restrictions of each of hypothesis and to develop more comprehensive models. This approach may be of use in developing novel inhibitor candidates as well as contributing a better understanding of structural characters of many compounds useful as anticancer agents targeting microtubules.

• Archives of Pharmacal Research
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• v.16 no.3
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• pp.254-256
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• 1993

For the evaluation of the role of .alpha., .betha.-unsaturated ketone portion of ar-tumerone for its activity, the structural variation of this structural unit was performed to omit its alkylating propery. Thus compounds 2, 3, and 4 were prepared and their cytotoxicities were determined against three different leukemiz cell lines (HL-60, K-562, and $L_{1210})$ in vitro. The biological inactivity against three different cell lines of these analogues implies that the $\alpha, \beta$-unsaturated ketone of ar-tumerone is the essential pharmacophore for its activity.

• Bulletin of the Korean Chemical Society
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• v.25 no.1
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• pp.69-72
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• 2004

The N-alkylation of 4-aminopyrimidine with a tetrahydro-3-aza-cyclopropa[c]inden-5-one, which is a model reaction of the pharmacophore of duocarmycins, was studied with a quantum chemical method. We consider two factors for the acceleration of the N-alkylation; distortion and protonation of the model pharmacophores. The distortion of the spirocyclopropyl moiety in the model spirocyclopropylcyclohexadienone could induce an intrinsic energy of 3-4 kcal/mol, but the protonation on the carbonyl oxygen of the model cyclohexadienone lowers the transition energy of the N-alkylation of 4-aminopyrimidine dramatically (~46 kcal/mol) and is considered to play a major role in the enzyme reaction. The distorted and protonated spirocyclohexadienone is exothermally relieved to a phenol with the heat of reaction of -37 kcal/mol. The protonation process is proposed to be the mode of action of duocarmycins in the DNA alkylation.

• Bulletin of the Korean Chemical Society
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• v.33 no.5
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• pp.1707-1714
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• 2012

Grb2 is an adapter protein involved in the signal transduction and cell communication. The Grb2 is responsible for initiation of kinase signaling by Ras activation which leads to the modification in transcription. Ligand based pharmacophore approach was applied to built the suitable pharmacophore model for Grb2. The best pharmacophore model was selected based on the statistical values and then validated by Fischer's randomization method and test set. Hypo1 was selected as a best pharmacophore model based on its statistical values like high cost difference (182.22), lowest RMSD (1.273), and total cost (80.68). It contains four chemical features, one hydrogen bond acceptor (HBA), two hydrophobic (HY), and one ring aromatic (RA). Fischer's randomization results also shows that Hypo1 have a 95% significant level. The correlation coefficient of test set was 0.97 which was close to the training set value (0.94). Thus Hypo1 was used for virtual screening to find the potent inhibitors from various chemical databases. The screened compounds were filtered by Lipinski's rule of five, ADMET and subjected to molecular docking studies. Totally, 11 compounds were selected as a best potent leads from docking studies based on the consensus scoring function and critical interactions with the amino acids in Grb2 active site.

• Bulletin of the Korean Chemical Society
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• v.34 no.9
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• pp.2707-2710
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• 2013

The present communication deals with development of ten novel N-Phenyl-3-Pyridin-2-yl imino derivatives as vascular smooth muscle relaxants. The derivatives were prepared and optimized using pocket modelling and pharmacophore modelling. The 4 hydroxy substituted derivatives are showed potent activity comparable to the sildenafil.