• Proceedings of the PSK Conference
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• 2000.04a
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• pp.158.1-158.1
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• 2000

• Bulletin of the Korean Chemical Society
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• v.35 no.7
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• pp.2065-2071
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• 2014

${\beta}$-Secretase (beta-amyloid converting enzyme 1 [BACE1]) is involved in the first and rate-limiting step of ${\beta}$-amyloid ($A{\beta}$) peptides production, which leads to the pathogenesis of Alzheimer's disease(AD). Therefore, inhibition of BACE1 activity has become an efficient approach for the treatment of AD. Ligand-based and docking-based 3D-quantitative structure-activity relationship (3D-QSAR) studies of acyl guanidine analogues were performed with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to obtain insights for designing novel potent BACE1 inhibitors. We obtained highly reliable and predictive CoMSIA models with a cross-validated $q^2$ value of 0.725 and a predictive coefficient $r{^2}_{pred}$ value of 0.956. CoMSIA contour maps showed the structural requirements for potent activity. 3D-QSAR analysis suggested that an acyl guanidine and an amide group in the $R_6$ substituent would be important moieties for potent activity. Moreover, the introduction of small hydrophobic groups in the phenyl ring and hydrogen bond donor groups in 3,5-dichlorophenyl ring could increase biological activity.

• Journal of Integrative Natural Science
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• v.7 no.1
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• pp.45-49
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• 2014

The (c-Jun N-terminal kinase 3) JNK3 is a potential therapeutic target for various neurological disorders. Here, a three dimensional quantitative structure-activity relationship (3D-QSAR) study on phenoxypyridine as JNK3 inhibitors was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The comparative molecular field analysis (CoMFA) using different partial atomic charges, was employed to understand the structural factors affecting JNK3 inhibitory potency. The Gasteiger-Marsili yielded a CoMFA model with cross-validated correlation coefficient ($q^2$) of 0.54 and non-cross-validated correlation coefficient ($r^2$) of 0.93 with five components. Furthermore, contour maps suggested that bulky substitution with oxygen atom in $R^3$ position could enhance the activity considerably. The work suggests that further chemical modifications of the compounds could lead to enhanced activity and could assist in the design of novel JNK3 inhibitors.

• Journal of Integrative Natural Science
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• v.13 no.4
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• pp.170-180
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• 2020

Abnormal regulation, hyperphosphorylation, and aggregation of the tau protein are the hallmark of several types of dementia, including Alzheimer's Disease. Increased activity of Glycogen Synthase Kinase-3β (GSK-3β) in the Central Nervous System (CNS), increased the tau hyperphosphorylation and caused the neurofibrillary tangles (NFTs) formation in the brain cells. Over the last two decades, numerous adenosine triphosphate (ATP) competitive inhibitors have been discovered that show inhibitory activity against GSK-3β. But these compounds exhibited off-target effects which motivated researchers to find new GSK-3β inhibitors. In the present study, we have collected the dataset of 31 C-Glycosylflavones derivatives that showed inhibitory activity against GSK-3β. Among the dataset, the most active compound was docked with the GSK-3β and molecular dynamics (MD) simulation was performed for 50 ns. Based on the 50 ns MD pose of the most active compound, the other dataset compounds were sketched, minimized, and aligned. The 3D-QSAR based Comparative Molecular Field Analysis (CoMFA) model was developed, which showed a reasonable value of q2=0.664 and r2=0.920. The contour maps generated based on the CoMFA model elaborated on the favorable substitutions at the R2 position. This study could assist in the future development of new GSK-3β inhibitors.

• Microbiology and Biotechnology Letters
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• v.27 no.1
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• pp.54-61
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• 1999

Measurement of inhibition of bioluminescence in Photobacterium phosphoreum has been porposed as a sensitive and rapid procedure to monitor toxic substances. However, at first, $EC_{50}$ which shows degree of toxicity to each toxic substances must be calculated. QSAR (Quantitative Structure Activity Relationship) model can be used to estimate $EC_{50}$ to save time and endeavor. Moderately high correlation coefficients ($r^2{\geq}$ 0.97) were calculated from the linear correlation between $EC_{50}$ and molecular connectivity indices of CAHs (chlorinated aliphatic hydrocarbons)such as $^0X$, $^0X^V$, $^1X$, $^2X$ and $^3X^v_c$ and quadratic correlation between $EC_{50}$ and $^0X$, $^0X^V$, $^2X^V$, $^3X_c$, $^3X^V_c$ and P. It shows that the molecular connection indices in carbon structure is contributed to biological characters with linear relation and that in the other one with quadratic relation. The $EC_{50}$ of chlorophenol derivatives had quadratic relation with the value of octanol/water prtition coefficients ($r^2$=0.99) and linear and quadratic relation with the number of chlorine compound (($r^2{\geq}$0.94). This confirms the already known trend of increasing toxicity with increasing ability of a compound to diffuse through cell membrane and number of chlorine substitution.

• Applied Biological Chemistry
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• v.51 no.3
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• pp.171-176
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• 2008

The comparative molecular similarity indices analysis (CoMSIA) models between 3${\beta}$-Hydroxy-12-oleanen-28-oic acid (1-30) analogues as substrate molecule and their inhibitory activities ($pI_{50}$) against protein tyrosine phosphatase (PTP)-1B were derived and discussed quantitatively. Listing in order, the CoMFA>CoMSIA${\geq}$HQSAR>2D-QSAR model, these QSAR models had the better statistical values. The optimized CoMSIA F1 model at grid 3.0${\AA}$ had the best predictability and fitness ($q^2$=0.754 and $r^2$=0.976) by field fit alignment. The order of contribution ratio (%) of CoMSIA fields concerning the inhibitory activities was a H-bond acceptor (48.9%), steric field (25.8%) and hydrophobic field (25.4%), respectively. Therefore, the inhibitory activities of substrate molecules against PTP-1B were dependent upon H-bond acceptor field (A) of $R_4$-group. From the analytical results of CoMSIA contour maps, oleanolic acid derivatives will have better inhibition activities if $R_1$ group has H-bond acceptor disfavor, $R_3$group has steric disfavor and $R_4$ group has steric, hydrophobic, H-bond favor.

• Bulletin of the Korean Chemical Society
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• v.34 no.3
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• pp.899-906
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• 2013

Using generated conformations from docking analysis by Gold algorithm, some 3D-QSAR models; CoMFA and CoMSIA have been created on 39 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues. These molecules inhibit the polymerization of tubulin into microtubules and thus they have been studied for the development of antitumor drugs. Training set for the CoMFA and CoMSIA models using 30 docked conformations gives $q^2$ Leave one out (LOO) values of 0.756 and 0.617, and $r^2$ ncv values of 0.988 and 0.956, respectively. The ability of prediction and robustness of the models were evaluated by test set, cross validation (leave-one-out and leave-ten-out), bootstrapping, and progressive scrambling approaches. The all-orientation search (AOS) was used to achieve the best orientation to minimize the effect of initial orientation of the structures. The docking results confirmed CoMFA and CoMSIA contour maps. The docking and 3D-QSAR studies were thoroughly interpreted and discussed and confirmed the experimental $pIC_{50}$ values.

• Journal of Photoscience
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• v.8 no.3_4
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• pp.119-121
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• 2001

Three-Dimensional Quantitative Structure-Activity Relationship(QSAR) has been investigated over 67 flavonoids to correlate and predict GI$\sub$50/ values. The partial least-squares(PLS) model was performed to calculate the activity of each derivatives, and this was compared with the actual value. The results of the cross-validated(${\gamma}$$^2$=0.997) values show that cytotoxic activities play an important role which is in good agreement with the observed GI$\sub$50/ values.

• Journal of Integrative Natural Science
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• v.8 no.4
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• pp.258-266
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• 2015

Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organs including 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 (CoMFA) 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 CoMFA 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 CoMFA models were generated using different alignments and the best model yielded a cross-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 CoMFA models was found to be $r^2_{pred}$0.653. The CoMFA study revealed that the $R_3$ position of the structure is important in influencing the biological activity of the inhibitors. Electro positive groups and bulkier substituents in this position enhance the biological activity.

• Bulletin of the Korean Chemical Society
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• v.27 no.11
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• pp.1919-1922
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• 2006