• Journal of Integrative Natural Science
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• v.9 no.2
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• pp.113-120
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• 2016

Monopolar spindle 1 (Mps1) is an attractive cancer target due to its high expression levels in a wide range of cancer cells. Mps1 is a dual specificity kinase. It plays an essential role in mitosis. The high expression od Mps1 was observed in various grades of breast cancers. In the current study, we have developed a CoMFA model of pyridazine derivatives as Mps1 kinase inhibitors. The developed CoMFA model ($q^2=0.797$; ONC=6; $r^2=0.992$) exhibited a good predictive ability. The model was then validated by Leave out five, progressive sampling and bootstrapping and found to be robust. The analysis of the CoMFA contour maps depicted favorable and unfavorable regions to enhance the activity. Bulky positive substitution at $R^3$ position and Negative substitution in $R^1$ position is favored could increase the activity. In contrast, bulky substitution in $R^1$ position is not favored. Our results can be used in designing a potent Mps1 (TTK) inhibitor.

• Journal of Integrative Natural Science
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• v.10 no.2
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• pp.95-104
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• 2017

Proviral Integration site of Moloney (Pim) murine Leukemia virus kinases is a serine/threonine specific protein kinase. It is largely involved in cell survival and proliferation. Pim-1 phosphorylates multiple cellular substrates to inhibit apoptosis and promote cell cycle progression. Over expression of Pim-1 kinase is observed in a range of malignancies and various solid cancers. High level of Pim-1 expression is seen in myeloma, acute myeloid leukemia, prostate cancer and liver carcinomas. Hence, Pim-1 is considered as an interesting cancer target. In the present study, we have performed region-focused CoMFA study on a series of imidazopyridazine derivatives as Pim-1 kinase inhibitors. A statistically acceptable region-focused CoMFA model ($q^2=0.571$; ONC=3; $r^2=0.909$) was developed. The model was then validated using Bootsrapping and progressive sampling. The contour map highlighted the regions favorable to increase the activity. Bulky substitutions in $R^2$ position of the phenyl ring could increase the activity. Similarly, small negative substitution in the $R^1$ position of the Pyridine ring could increase the activity considerably. Our results will be useful to design novel Pim-1 kinase inhibitors of this series.

• Toxicological Research
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• v.33 no.3
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• pp.173-182
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• 2017

In silico methods to predict toxicity include the use of (Quantitative) Structure-Activity Relationships ((Q)SARs) as well as grouping (category formation) allowing for read-across. A challenging area for in silico modelling is the prediction of chronic toxicity and the No Observed (Adverse) Effect Level (NO(A)EL) in particular. A proposed solution to the prediction of chronic toxicity is to consider organ level effects, as opposed to modelling the NO(A)EL itself. This review has focussed on the use of structural alerts to identify potential liver toxicants. In silico profilers, or groups of structural alerts, have been developed based on mechanisms of action and informed by current knowledge of Adverse Outcome Pathways. These profilers are robust and can be coded computationally to allow for prediction. However, they do not cover all mechanisms or modes of liver toxicity and recommendations for the improvement of these approaches are given.

• Journal of Integrative Natural Science
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• v.10 no.3
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• pp.141-147
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• 2017

Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis, which is the formation of new blood vessels from pre-existing vessels. Consequently, blocking of the vascular endothelial growth factor receptor (VEGFR-2) by small molecule inhibitors leads to the inhibition of cancer induced angiogenesis. In this study, we performed a two dimensional quantitative structure activity relationship (2D-QSAR) study of 38 N-Phenyl-N'-{4-(4-quinolyloxy) phenyl} urea derivatives as VEGFR-2 inhibitors based on hologram quantitative structure-activity (HQSAR). The model developed showed reasonable $q^2=0.521$ and $r^2=0.932$ values indicating good predictive ability and reliability. The atomic contribution map analysis of most active compound (compound 7) indicates that hydrogen and oxygen atoms in the side chain of ring A and oxygen atom in side chain of ring C contributes positively to the activity of the compounds. The HQSAR model developed and the atomic contribution map can serve as a guideline in designing new compounds for VEGFR-2 inhibition.

• Reproductive and Developmental Biology
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• v.29 no.1
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• pp.43-48
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• 2005

To search of a new porcine pheromonal odorants for biostimulation control system technologies to offer a potentially useful and practical way to improve reproductive efficiency in livestock species, the holographic quantitative structure activity relationship (HQSAR) model between odorants, 2-phenoxytetrahydrofurane (A), 2-cyclohexyl-oxytetrahydrofurane (B), derivatives and binding affinity constants (p[Od.]/sub 50/) for porcine odorant-binding protein (pOBP) as receptor of pig pheromones were derivated and disscused. The binding affinity constants of cyclohexyl substituents (A) for pOBP were higher (A>B) than that of phenyl substituents (B). It was revealed that the optimum HQSAR model XI using PLS analyses had a fragment length (5∼8) with chirality at 5 components and hologram length 97 bin, which had a cross-validated q²(predictablities) of 0.916, and a conventional correlation coefficient r² (fitness) of 0.988, respectively. From the atomic contribution, the C3 and C5 atom in 2-oxyfuryl group contributed to binding affinity constants, whereas the central carbon atom in tert-butyl group on the cyclohexyl ring and the C4 atom of furyl group parts showed no contribution.

• Archives of Pharmacal Research
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• v.27 no.9
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• pp.893-900
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• 2004

2- or 6-Substituted BZT-N derivatives were synthesized, and their cytotoxic activity against can-cer L1210 and SNU-1 cells was examined. The antitumor action was also assessed in mice bearing S-180 cells in peritoneal cavity. In a comparison, it was found that 6-substituted BZT-N derivatives exhibited higher potencies in both bioactivities than 2-substituted BZT-N derivatives against L1210 cells in in vitro and S-180 in vitro tests exception of compound 36. Interestingly, it was observed that 2-substituted compound 36, which has methyl group at RI position, exhib-ited a better antitumor activity than 6-substituted compounds against L1210 and SNU-1 in vitro. The EDso value of 2-substituted compound 36 against L1210 was found to be comparable to the EDso value of adriamycin and was even better against the solid cancer cell line SNU-1. It was also observed that 2-substituted compound 36 showed better antitumor activity in mice bearing S-180 cells in the peritoneal cavity. The T/C (％) value of 2-substituted compound 36 was simi-lar to that of adriamycin. Quantitative structure-activity relationship (QSAR) tests reveal that the experimental E $D_{50}$ values against SNU-1 closely correlate with both the calculated HOMO ener-gies ( $E_{HOMO}$) and the measured H-NMR chemical shift of 3-H ($\delta$$_{H}$). The results suggests that a compound having higher $E_{HOMO}$ and $\delta$$_{H}$ values usually should have a lower E $D_{50}$ (SNU-1) value.lue.lue.lue.

• Applied Biological Chemistry
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• v.51 no.1
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• pp.38-43
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• 2008

3D-QSARs on the fungicidal activity with N-phenylbenzenesulfonamide and N-phenyl-2-thienylsul-fonamide analogues (1-34) against Fusarium wilt (Fusarium oxysporum) were discussed quantitatively using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods, respectively. Generally, the CoMFA models have better predictability and fitness than the CoMSIA models. The fungicidal activities, according to the information of the optimized CoMF A 2 model $(r^2\;_{cv.}=0.523\;&\;r^2\;_{ncv.}=0.956)$, were dependent on the electrostatic field of the N-phenylbenzenesulfonamide analogues. Therefore, from the results of graphical analyses on the contour maps with the optimized CoMFA 2 model, it is expected that the characters of $R_4-substituents$ on the N-phenyl ring as steric and positive charge favor will contribute to the fungicidal activity against Fusarium wilt.

• YAKHAK HOEJI
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• v.54 no.5
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• pp.328-333
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• 2010

Comparative molecular field analyses (CoMFA) on the antiproliferative activity of N-substituted (R) 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole analogues (ADTs: 1-17) against bladder cancer (HCV29T) and rectal cancer (SW707) cells were studied quantitatively. The statistical predictability and fitness of CoMFA A1 model for bladder cancer cells were better than those of CoMFA F1 model for rectal cancer cells and the antiproliferative activity of ADTs depends on steric field (HCV29T: 93.1% & SW707: 83.8%). Also, from the contour maps of optimized CoMFA models, the activity for bladder cancer cells had predicted to increase when sterically favored groups were substituted on meta- and para-position, and sterically disfavored groups were substituted on one ortho-position of phenyl ring. The activity for rectal cancer cells had predicted to increase when sterically favored groups were substituted on para-position, and sterically disfavored groups were substituted on two ortho-position of phenyl ring as R-group.

• Journal of Applied Biological Chemistry
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• v.53 no.2
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• pp.99-104
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• 2010

The influences on antioxidant activities of the substituents ($R_1-R_4$) on benzo ring in 4-Methyl-2H-benzopyran-2-one analogues (1-23) were discussed quantitatively using three dimensional quantitative structure-activity relationships (3D-QSARs: Comparative molecular field analyses (CoMFA) and Comparative molecular similarity indice analyses (CoMSIA)) methods. The statistical qualities of CoMSIA models were better than those of CoMFA models and the CoMSIA 2 model was optimized model ($q^2$=0.700 & $r^2$=0.979). Also, the contribution ratios (%) of the optimized CoMSIA 2 model were H-bond donor field 43.5%, electrostatic field 41.8% and steric field 14.7% so that the antioxidant activity exhibited a strong correlation with H-bond donor and electrostatic factor of molecules. From the analytical results of the CoMSIA contour maps, if the positive charge favor group and H-bond donor disfavor group were placed in the $R_1-R_4$ positions on the benzo ring, it was predicted that the groups would raised the antioxidant activity.

• Applied Biological Chemistry
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• v.48 no.4
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• pp.394-399
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• 2005

The comparative molecular field analyses (CoMFA) models for the herbicidal activities against barnyardgrass (Echinochloa crus-galli) and rice plant (Orysa sativa L.) by the substituent (R) on the hexahydroisoindol-1-one ring in a series of new 2-(4-chloro-5-(2-chloroallyloxy)-2-fluorophenyl)-3-thioalkoxy-2,3,4,5,6,7-hexahydroisoindol-1-one derivatives were conducted and discussed for selectivity between both plants. The statistical results of the two best models (B2 & R7) showed the best predictability for the herbicidal activities based on the cross-validated value $q_2(r^2cv.=0.529{\sim}0.755)$ and none cross-validated value $({r^2}_{ncv.}=0.937{\sim}0.945)$, respectively. Based on the findings, the predictability and fitness of the model (B2) for barnyard grass was better than that of the model (R7) for rice plant. From the two models and contour maps, it is revealed that the novel selective character for herbicidal activity between the two plants depend on the electrostatic field and steric field for the substituent of ortho-positions on the S-phenyl group as R-substituent in hexahydroisoindol-1-one ring.