• Bulletin of the Korean Chemical Society
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• 제27권2호
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• pp.273-276
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• 2006

Three dimensional quantitative structure-activity relationship studies for a series of isatin derivatives as a nonpeptidyl caspase-3 enzyme inhibitor were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The first approach of non-peptidyl small molecules by 3D QSAR may be useful in guiding further development of potent caspase-3 inhibitors.

• Bulletin of the Korean Chemical Society
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• 제33권1호
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• pp.149-152
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• 2012

The (S)-(+)-decursin and its analogues are reported as potent inhibitors of melanin production in B16 murine melanoma cells. In order to understand the factors responsible for potency as well as inhibition of potency of (S)-(+)-decursin and its analogues, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Since receptor structures are not available, a pharmacophore model was constructed. Using PHASE, we generated 3 different models and selected the seven-site model, which returned excellent statistical values ($r^2$ = 0.9127, $Q^2$ = 0.6878, Pearson-R = 0.9014). Using the generated pharmacophore model, we screened a natural products library and obtained 4'-epi-decursin as the most related compound. 4'-epidecursin is similar to (S)-(+)-decursin, but shows additional interaction possibilities with tyrosinase. The study thus sheds some light on possibility of developing more potent tyrosinase inhibitors.

• The Korean Journal of Physiology and Pharmacology
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• 제17권3호
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• pp.237-243
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• 2013

B13 is a ceramide analogue and apoptosis inducer with potent cytotoxic activity. A series of arylpropyl sulfonamide analogues of B13 were evaluated for their cytotoxicity using MTT assays in prostate cancer PC-3 and leukemia HL-60 cell lines. Some compounds (4, 9, 13, 14, 15, and 20) showed stronger activities than B13 in both tumor cell lines, and compound (15) gave the most potent activity with $IC_{50}$ values of 29.2 and 20.7 ${\mu}M$, for PC-3and HL-60 cells, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed to build highly reliable and predictive CoMSIA models with cross-validated $q^2$ values of 0.816 and 0.702, respectively. Our results suggest that long alkyl chains and a 1R, 2R configuration of the propyl group are important for the cytotoxic activities of arylpropyl sulfonamides. Moreover, the introduction of small hydrophobic groups in the phenyl ring and sulfonamide group could increase biological activity.

• Molecular & Cellular Toxicology
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• 제2권3호
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• pp.216-221
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• 2006

The cholinesterase-inhibiting organophosphorous (OP) compounds known as nerve agents are highly toxic. The principal toxic mechanism of OP compounds is the inhibition of acethylcholine esterase (AChE) by phosphorylation of its catalytic site. The reversible competitive inhibition of AChE may prevent the subsequent OP intoxication. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) was performed to investigate the relationship between the 29 compounds with structural diversity and their bioactivities against AChE. In particular, predictive models were constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results indicate reasonable model for CoMFA ($q^{2}=0.453,\;r^{2}=0.697$) and CoMSIA ($q^{2}=0.518,\;r^{2}=0.696$). The presence of steric and hydophobic group at naphtyl moiety of the model may lead to the design of improved competitive inhibitors for organophosphorous intoxication.

• 통합자연과학논문집
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• 제8권1호
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• pp.40-47
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• 2015

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a promising target in drug discovery. It is involved in multiple cellular processes and associated with the pathogenesis of several diseases. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of GSK-3 inhibitors to understand the structural basis for inhibitory activity. Comparative molecular field analysis (CoMFA) method was used to derive 3D-QSAR models. A reliable CoMFA model was developed using ligand-based alignment scheme. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.594 and a non-cross-validated correlation coefficient ($r^2$) of 0.943. Robustness of the model was checked by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel compounds with enhanced GSK-3 inhibitory activity.

• Bulletin of the Korean Chemical Society
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• 제30권11호
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• pp.2739-2748
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• 2009

Hologram and three dimensional quantitative structure activity relationship (3D QSAR) studies for a series of anilinobipyridine JNK3 inhibitors were performed using various alignment-based comparative molecular field analysis (COMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro JNK3 inhibitory activity exhibited a strong correlation with steric and electrostatic factors of the molecules. Using four different types of alignments, the best model was selected based on the statistical significance of CoMFA ($q_2\;=\;0.728,\;r_2\;=\;0.865$), CoMSIA ($q_2\;=\;0.706,\;r_2\;=\;0.960$) and Hologram QSAR (HQSAR: $q_2\;=\;0.838,\;r_2\;=\;0.935$). The graphical analysis of produced CoMFA and CoMSIA contour maps in the active site indicated that steric and electrostatic interactions with key residues are crucial for potency and selectivity of JNK3 inhibitors. The HQSAR analysis showed a similar qualitative conclusion. We believe these findings could be utilized for further development of more potent and selective JNK3 inhibitors.

• The Korean Journal of Physiology and Pharmacology
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• 제17권6호
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• pp.517-523
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• 2013

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with $IC_{50}$ values of 0.7, 0.1, and $5.1{\mu}M$, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa ($q^2$, 0.857; $r^2$, 0.984; $r^2\;_{pred}$, 0.966), HL-60 ($q^2$, 0.777; $q^2$, 0.937; $r^2\;_{pred}$, 0.913), and PC-3 ($q^2$, 0.702; $q^2$, 0.983; $r^2\;_{pred}$, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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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.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.247.2-248
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• 2003

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) was applied to 62 derivatives known as COX-2 selective inhibitors. Partial least square (PLS) analyses produced good predicted models with q2 value of 0.803 (s=0.285, F=215.401, r2=0.951) and 0.769 (s=0.192, F=245.364, r2=0.980) for CoMFA and CoMSIA, respectively. (omitted)

• 한국생물정보학회:학술대회논문집
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• 한국생물정보시스템생물학회 2005년도 BIOINFO 2005
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• pp.249-255
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• 2005

Angiotensin-converting enzyme (ACE) is primarily responsible for human hypertension. Current ACE drugs show serious cough and angiodema health problems due to the un-specific activity of the drug to ACE protein. The availability of ACE crystal structure (1UZF) provided the plausible biological orientation of inhibitors to ACE active site (C-domain). Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecula. field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of 28 ACE inhibitors. Alignment for CoMFA obtained by docking ligands to 1UZF protein using FlexX program showed better statistical model as compared to superposition of corresponding atoms. The statistical parameters indicate reasonable models for both CoMFA (q$^2$ = 0.530, r$^2$ = 0.998) and CoMSIA (q$^2$= 0.518, r$^2$ = 0.990). The 3D-QSAR analyses provide valuable information for the design of ACE inhibitors with potent activity towards C-domain of ACE. The group substitutions involving the phenyl ring and carbon chain at the propionyl and sulfonyl moieties of captopril are essential for specific activity to ACE.