• Journal of Integrative Natural Science
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• v.4 no.4
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• pp.266-272
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• 2011

Focal adhesion kinase (FAK) is a potential target for the treatment of primary cancers as well as prevention of tumor metastasis. To understand the structural and chemical features of FAK inhibitors, we report comparative molecular field analysis (CoMFA) for the series of 7H-pyrrolo(2,3-d)pyrimidines. The CoMFA models showed good correlation between the actual and predicted values for training set molecules. Our results indicated the ligand-based alignment has produced better statistical results for CoMFA ($q^2$ = 0.505, $r^2$ = 0.950). Both models were validated using test set compounds, and gave good predictive values of 0.537. The statistical parameters from the generated 3D-QSAR models were indicated that the data are well fitted and have high predictive ability. The contour map from 3D-QSAR models explains nicely the structure-activity relationships of FAK inhibitors and our results would give proper guidelines to further enhance the activity of novel inhibitors.

• The Korean Journal of Pesticide Science
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• v.7 no.2
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• pp.75-82
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• 2003

We discuss that the growth inhibition activities against root and shoot of rice plant (Oryza sativa L.) and barnyard grass (Echinochloa crus-galli) by N-phenyl-3,4,5,6-tetrahydrophthalimide (A) and N-phenyl-3,4-dimethylmaleimide (B) derivatives with changing substituents can be explained and predicted using comparative molecular field analyses (CoMPA) method. And the results show that the cross-validation value, $q^2$ at three components and Pearson correlation coefficient, $r^2$ were rice plant: shoot; $r^2=0.987$, $q^2=0.387$ & root; $r^2=0.923$, $q^2=0.307$ and barnyard grass: shoot; $r^2=0.902$, $q^2=0.535$ & root; $r^2=0.900$, $q^2=0.450$, respectively. In addition, The activities of unknown compounds were predicted by CoMFA method. From the contour map of (A) derivatives, the selective factors to remove barnyard grass takes positive charge on the benzylic carbon atom (C27), negative charged carbon atom (C29) of meta position and steric bulky groups on the cyclic imino ring (C7-C8).

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.441-447
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• 2010

B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with $IC_{50}$ values of 36 and $9\;{\mu}M$, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated $q^2$ values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity.

• Bulletin of the Korean Chemical Society
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• v.29 no.8
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• pp.1499-1504
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• 2008

Pyrazine derivatives bind to b-RAF receptor which is important in cancer therapy. The ligand-receptor interactions have been studied by comparative molecular field analysis (CoMFA) and molecular docking methods. Applying conventional ligand-based alignment schemes for the whole set was not successful. However, QM and DFT results suggested that some ligands have electrostatic interaction while others have steric interactions. On the basis of these results, we divided the dataset into two subsets. Electrostatic effect was found to be important in one set while steric effect for the other. Best docking modes were obtained for each subset based on the available crystal structure. These receptor-guided CoMFA models propose an interesting possibility which is difficult to obtain otherwise. i.e., in one binding mode the electrostatic interaction plays a key role for one subset ($q^2$ = 0.46, $r^2$ = 0.98), while in another binding mode steric effect is important with another subset ($q^2$ = 0.43, $r^2$ = 0.74).

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.186.3-186.3
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• 2003

The three-dimensional quantitative structure-activity relationship (3D-QSAR) study using the comparative molecular field analysis (CoMFA) was performed on indolinones derivatives as an inhibitor of the protein tyrosine kinase of fibroblast growth factor receptor (FGFR). In the training set, twenty-four indolinone derivatives were aligned based on the indole fragment and the steric and electrostatic fields were included in the analysis. The best predicted model showed the cross-validated coefficient (r$^2$$\sub$cv/) of 0.804 and bib-cross validated coefficient (r$^2$) of 0.942. The CoMFA study can be used to predict several new inhibitors of the FGFR.

• Bulletin of the Korean Chemical Society
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• v.34 no.8
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• pp.2387-2393
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• 2013

Benzotriazole is an important synthetic auxiliary for potential clinical applications. A series of benzotriazoles as potential antiproliferative agents by inhibiting histone deacetylase (HDAC) were recently reported. Three-dimensional quantitative structure-activity relationship (3D-QSAR), including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were performed to elucidate the 3D structural features required for the antiproliferative activity. The results of both ligand-based CoMFA model ($q^2=0.647$, $r^2=0.968$, ${r^2}_{pred}=0.687$) and CoMSIA model ($q^2=0.685$, $r^2=0.928$, ${r^2}_{pred}=0.555$) demonstrated the highly statistical significance and good predictive ability. The results generated from CoMFA and CoMSIA provided important information about the structural characteristics influence inhibitory potency. In addition, docking analysis was applied to clarify the binding modes between the ligands and the receptor HDAC. The information obtained from this study could provide some instructions for the further development of potent antiproliferative agents and HDAC inhibitors.

• 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.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.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.

• 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.