• Journal of Applied Biological Chemistry
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• v.53 no.4
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• pp.225-231
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• 2010

To understand the inhibitory activity with changing hydroxyl substituents ($R_l-R_9$) of polyhydroxy substituted 2-phenyl-l,4-benzopyrone analogues (1-25) against tyrosinase (PDB ID: oxy-form; 1WX2), molecular docking and the three dimensional quantitative structure-activity relationships (3D-QSARs: Comparative molecular field analysis (CoMFA) & Comparative molecular similarity indices analysis (CoMSIA)) were studied quantitatively. The statistically best models were CoMFA 1 and CoMSIA 1 model from the results. The optimized CoMSIA 1 model with the sensitivity of the perturbation and the prediction produced ($dq^2'/dr_{yy'}^2$=1.009 & $q^2$=0.51l) by a progressive scrambling analysis were not dependent on chance correlation. The inhibitory activities with optimized CoMSIA 1 model were dependent upon electrostatic factor (51.4%) of substrate molecules. Contour mapping the 3D-QSAR models to the active site of tyrosinase provides new insight into the interaction between tyrosinase as receptor and 2-phenyl-l,4-benzopyrone analogues as inhibitor. Therefore, the results will he able to apply to the optimization of a new potent tyrosinase inhibitors.

• Bulletin of the Korean Chemical Society
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• v.31 no.5
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• pp.1361-1367
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• 2010

A series of O,O-dialkyl-1-phenoxyacetoxy-1-methylphosphonate analogues (1~22) as a new class of potent inhibitors of pyruvate dehydrogenase were synthesized and 3D-QSARs (three dimensional qantitative structure-activity relationships) models on the pre-emergency herbicidal activity against the seed of cucumber (Cucumus Sativa L.) were derived and discussed quantitatively using comparative molecular field analysis (CoMFA) and comparative molecular similarity indeces analysis (CoMSIA) methods. The statistical values of CoMSIA models were better predictability and fitness than those of CoMFA models. The inhibitory activities according to the optimized CoMSIA model I were dependent on the electrostatic field (41.4%), the H-bond acceptor field (26.0%), the hydrophobic field (20.8%) and the steric field (11.7%). And also, it was found that the optimized CoMSIA model I with the sensitivity to the perturbation ($d_q{^{2'}}/dr^2{_{yy'}}$ = 0.830) and the prediction ($q^2$ = 0.503) produced by a progressive scrambling analyses were not dependent on chance correlation. From the results of graphical analyses on the contour maps with the optimized CoMSIA model I, it is expected that the structural distinctions and descriptors that subscribe to herbicidal activities will be able to apply new an herbicide design.

• Bulletin of the Korean Chemical Society
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• v.32 no.5
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• pp.1604-1612
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• 2011

We developed three-dimensional quantitative structure activity relationship (3D-QASR) models for 17 adamantyl derivatives as P-glycoprotein (P-gp) inhibitors. Eighteen different partial charge calculation methods were tested to check the feasibility of the 3D-QSAR models. Best predictive comparative molecular field analysis (CoMFA) model was obtained with the Austin Model 1-Bond Charge Correction (AM1-BCC) atomic charge. The 3D-QSAR models were derived with CoMFA and comparative molecular similarity indices analysis (CoMSIA). The final CoMFA model ($q^2$ = 0.764, $r^2$ = 0.988) was calculated with an AM1-BCC charge and electrostatic parameter, whereas the CoMSIA model ($q^2$ = 0.655, $r^2$ = 0.964) was derived with an AM1-BCC charge and combined steric, electrostatic, hydrophobic and HB-acceptor parameters. Leave-five-out (LFO) cross-validation was also performed, which yielded good correlation coefficient for both CoMFA (0.801) and CoMSIA (0.656) models. Robustness of the developed models was checked further with 1000 run bootstrapping analyses, which gave an acceptable correlation coefficient for CoMFA (BS-$r^2$ = 0.997, BS-SD = 0.003) and CoMSIA (BS-$r^2$ = 0.996, BS-SD = 0.018).

• Bulletin of the Korean Chemical Society
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• v.25 no.10
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• pp.1525-1530
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• 2004

Mutagen X (MX) exists in our drinking water as the bi-products of chlorine disinfection. Being one of the most potent mutagen, it attracted much attention from many researchers. MX and its analogs are synthesized and modeled by quantitative structure activity relationship (QSAR) methods. As a result, factors affecting this class of compounds have been found to be steric and electrostatic effects. We tried to collect all the data available from the literature. With both CoMFA and CoMSIA various combinations of physiochemical parameters were systematically studied to produce reasonable 3-dimensional models. The best model for CoMFA gave $q^2$ = 0.90 and $r^2$ = 0.97, while for CoMSIA $q^2$ = 0.85 and $r^2$ = 0.94. So the models seem to be reasonable. Unlike previous result of CoMFA, in our case steric parameter alone gave the best statistics. Although the steric contribution was found to be the most important in both CoMFA and CoMSIA, steric parameter along with electrostatic parameter produced slightly better model in CoMSIA. Overall, steric contribution is clearly the most important single factor. However, when we compare chlorine and bromine substitution, chlorine substitution can be more mutagenic. This indicates that other factors such as electrostatic effect also influence the mutagenicity. From the contour maps, steric contribution seems to be focused on rather small area near C6 substituent of the furanone ring, rather than C3 substituent. Therefore the locality of steric contribution can play a significant role in mutagenicity.

• Journal of Integrative Natural Science
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• v.9 no.3
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• pp.190-198
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• 2016

Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organsincluding the liver, gut, lung, kidney, heart, brain and plasma. It is involved in gout pathogenesis. In this study, we have performed Comparative Molecular Field Analysis (CoMSIA) on a series of 2-(indol-5-yl) thiazole derivatives as xanthine oxidase (XO) inhibitors to identify the structural variations with their inhibitory activities. Ligand based CoMSIA models were generated based on atom-by-atom matching alignment. In atom-by-atom matching, the bioactive conformation of highly active molecule 11 was generated using systematic search. Compounds were aligned using the bioactive conformation and it is used for model generation. Different CoMSIA models were generated using different alignments and the best model yielded across-validated $q^2$ of 0.698 with five components and non-cross-validated correlation coefficient ($r^2$) of 0.992 with Fisher value as 236.431, and an estimated standard error of 0.068. The predictive ability of the best CoMSIA models was found to be $r{^2}_{pred}$ 0.653. The study revealed the important structural features required for the biological activity of the inhibitors and could provide useful for the designing of novel and potent drugs for the inhibition of Xanthine oxidase.

• Reproductive and Developmental Biology
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• v.30 no.3
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• pp.169-174
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• 2006

To search of a new porcine pheromonal odorants, the comparative molecular similarity indices analysis(CoMSIA) between porcine odorant binding protein(pOBP) as receptor and ligands of green odorants 2-(Cyclohexyloxy)tetrahydrofurane derivatives as substrate molecule were conducted and disscused quantitatively. In the optimized CoMSIA model(I-AI) with chirality($I:\;C_{1'}(R),\;C_2(S)$) in substrate molecules and atom based fit alignment(AE) of the odorants the statistical PLS results showed the best predictability of the binding affinities based on the LOO cross-validated value ${r^2}_{cv.}\;(q^2=0.856)$ and non cross-validated conventional coefficient(${r^2}_{ncv.}=0.964)$). The structural distinctions of the highest active molecules were able to understand from the interaction between pOBP and green odorants in the contour maps with CoMSIA model.

• Proceedings of the SCSK Conference
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• 2003.09a
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• pp.733-740
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• 2003

To find a new substance with superior melanogenesis inhibitory activity, the bioactivities of alkyl-3,4-dihydroxy-5-substituted benzoate (A) and N-alkyl-3,4-dihydroxy-5-substituted benzamide (B) derivatives as substrate of tyrosinase were measured in mouse melanoma cells. And the bioactivities analyzed using comparative molecular similarity indices analysis (CoMSIA). From the CoMSIA model, when cross-validation value (q$^2$) is 0.713 at four components, the pearson correlation coefficient ($r^2$) is 0.900. Unknown compounds were predicted, using QSAR analyzed results from the CoMSIA methods. Excellent agreement was obtained between the measured and the predicted bioactivities of unknown compounds. As the results of prediction from CoMSIA, we could conclude that the bioactivities were increased from pl$_{50}$=3.18-4.80 to above 5.17 by creation of 6-methylheptyl, n-pentylphenyl and 2-hydroxypentylphenyl group etc,.,.

• Bulletin of the Korean Chemical Society
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• v.27 no.11
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• pp.1741-1746
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• 2006

3D-QSARs on the neuroblocking activities by 1-(6-chloro-3-pyridylmethyl)-2-nitroiminoimidazolidine analogues as agonist at the nicotinic acetylcholine receptor (nAChR) were studied quantitatively using CoMFA and CoMSIA methodologies. The statistical results of CoMFA (A5: $r^2\;_{cv.}\;=\;0.707\;&\;r^2\;_{ncv.}$= 0.986) and CoMSIA model (A3: $r^2\;_{cv.}$ = 0.715 & $r^2\;_{ncv.}$ = 0.961) showed the best predictability and fitness for neuroblocking activity based on the cross-validated value and non-cross validated value. The steric and H-bond acceptor nature of a compound were essential for high activity. The study on 3D-QSARs between substrate molecules and their neuroblocking activities appears to be an useful approach for designing better neuroblocking drug development.

• Bulletin of the Korean Chemical Society
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• v.26 no.12
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• pp.1941-1945
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• 2005

To raises the possibility of designing effective inhibitors, 3D-QSAR for the inhibition of calcineurin-NFAT signaling by new N-(4-oxo-1(4H)-naphthalenylidene benzenesulfonamide derivatives as inhibitors of intracellular protein-protein interactions were studied using CoMFA and CoMSIA methodology. The three templates, N-(4-oxo-1(4H)-naphthalenylidene)benzenesulfonamide (A), benzenesulfonamide (B) and 4-oxo-1(4H)-naphthalenylidene (C) were selected to improve the statistic of the present 3D-QSAR models. The best models with combination of standard field in CoMFA, and steric field and electrostatic field in CoMSIA derived from the template, B and C, because most of the compounds tend not to be aligned in template A. From the based on the CoMFA and CoMSIA contour maps, the $R_1$ and $R_2$ groups on 4-oxo-1(4H) naphthalenylidene ring are steric favor. The ortho position on the benzenesulfonyl ring is steric disfavor and the meta position is steric favor. In addition, the oxygene atom of carbonyl group will have better inhibition activities as it has a negative charge favor. From these findings, we can conclude that the analyses of the contour maps provided insight into possible modification of molecules for effective inhibitiors.

• Bulletin of the Korean Chemical Society
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• v.25 no.12
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• pp.1801-1806
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• 2004

Ligand-based quantitative structure-activity relationship (QSAR) studies were performed on indolinones derivatives as a potential inhibitor of the protein tyrosine kinase of fibroblast growth factor receptor (FGFR) by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) implemented in the SYBYL packages. The initial X-ray structure of docked ligand (Su5402) to FGFR was used to minimize the 27 training set molecules using TRIPOS force field. Seven models were generated using CoMFA and CoMSIA with grid spacing 2 ${\AA}$. After the PLS analysis the best predicted CoMSIA model with hydrophobicity, hydrogen bond donor and acceptor property showed that a leave-one out(LOO) cross validated value $({r^2}_{cv})^$ and non-cross validated conventional value $({r^2}_{ncv})^$ are 0.543 and 0.938, respectively.