• Journal of Integrative Natural Science
• /
• v.5 no.1
• /
• pp.6-12
• /
• 2012

c-Jun N-terminal kinase-3 (JNK-3) has been identified as a promising target for neuronal apoptosis and has the effective therapeutic for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and other CNS disorders. Herein, we report the essential structural and chemical parameters for JNK-3 inhibitors utilizing comparative molecular field similarity indices analysis (CoMSIA) using the derivatives of 3,5-disubstituted quinolines. The best predictions were obtained CoMSIA model (q2=0.834, r2=0.987) and the statistical parameters from the generated 3D-QSAR models were indicated that the data are well fitted and have high predictive ability. The resulting contour map from 3D-QSAR models might be helpful to design novel and more potent JNK3 derivatives.

• Bulletin of the Korean Chemical Society
• /
• v.29 no.3
• /
• pp.647-655
• /
• 2008

Microsomal prostaglandin E2 synthase (mPGES-1) is a potent target for pain and inflammation. Various QSAR (quantitative structure activity relationship) analyses used to understand the factors affecting inhibitory potency for a series of MK886 analogues. We derived four QSAR models utilizing various quantum mechanical (QM) descriptors. These QM models indicate that steric, electrostatic and hydrophobic interaction can be important factors. Common pharmacophore hypotheses (CPHs) also have studied. The QSAR model derived by best-fitted CPHs considering hydrophobic, negative group and ring effect gave a reasonable result (q2 = 0.77, r2 = 0.97 and Rtestset = 0.90). The pharmacophore-derived molecular alignment subsequently used for 3D-QSAR. The CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) techniques employed on same series of mPGES-1 inhibitors which gives a statistically reasonable result (CoMFA; q2 = 0.90, r2 = 0.99. CoMSIA; q2 = 0.93, r2 = 1.00). All modeling results (QM-based QSAR, pharmacophore modeling and 3D-QSAR) imply steric, electrostatic and hydrophobic contribution to the inhibitory activity. CoMFA and CoMSIA models suggest the introduction of bulky group around ring B may enhance the inhibitory activity.

• Proceedings of the Korean Society for Bioinformatics Conference
• /
• 2005.09a
• /
• pp.249-255
• /
• 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.

• Bulletin of the Korean Chemical Society
• /
• v.26 no.6
• /
• pp.952-958
• /
• 2005

Angiotensin-converting enzyme (ACE) is known to be primarily responsible for hypertension. Threedimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of 28 ACE inhibitors. The availability of ACE crystal structure (1UZF) provided the plausible biological orientation of inhibitors to ACE active site (C-domain). 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 better activity against ACE.

• Bulletin of the Korean Chemical Society
• /
• v.30 no.3
• /
• pp.613-617
• /
• 2009

3D-QSARs for the inhibition activities against protox by herbicidal 2-N-phenylisoindolin-1-one derivatives were studied quantitatively using CoMFA and CoMSIA methods. The result of the statistical quality of optimized CoMSIA model 2 ($FF:\;{r^2}_{cv.};\;0.973\;&\;{r^2}_{ncv.};\;0.612$) was higher than that of CoMFA model 1 ($AF:\;{r^2}_{cv.};\;0.414\;&\;{r^2}_{ncv.};\;0.909$). Also, the relative contribution of the optimized CoMSIA model 2 showed the steric (24.6%), electrostatic (31.0%), hydrophobic (ClogP, 23.4%) and H-bond acceptor field (21.0%), respectively. From the results of the contour maps, the protox inhibition activities are expected to increase when steric favor and H-bond acceptor favor groups are substituted on $R_2$ position and positive favor group are substituted on $C_2,\;C_3,\;and\;C_5$ atom in phenyl ring of $R_2$ position. And the inhibition activities are expected to increase when hydrophobic favor group is substituted on $C_1,\;C_3$ atom in phenyl ring of $R_2$ position and $C_1$ atom of $R_2$ position and hydrophilic favor groups are substituted on $C_4$ atom in phenyl ring of $R_1$ position and the terminal group of $R_1$ position.

• Applied Biological Chemistry
• /
• v.50 no.3
• /
• pp.192-197
• /
• 2007

3D-QSARs on the fungicidal activity of N-phenylbenzenesulfonamide and N-phenyl-2-thienylsulfonamide analogues (1-37) against Phytophthora blight (Phytophthora capsici) were studied quantitatively using CoMFA and CoMSIA methods. The statistical results of the optimized CoMFA (2) model ($r^2_{cv.}(q^2)$ = 0.692 & $r^2_{ncv.}$= 0.965) show better predictability and fitness than CoMSIA (2) model ($r^2_{cv.}(q^2)$ = 0.796 & $r^2_{ncv.}$= 0.958). The fungicidal activities according to the information of the optimized CoMFA (2) model were dependent upon the steric and electrostatic fields of the molecules. Therefore, from the contribution contour maps of CoMFA (2) model, it is expected that 63% contribution was caused by the steric bulk of meta-substituent ($R_1$) on the S-phenyl ring. Also, the other contribution level of 32.9% was represented by the positive charged $R_4-group$ ($R_1$) on the N-phenyl ring and para-substituent ($R_1$) on the S-phenyl ring. A series of higher active compounds, $R_1$= 3-decyl substituent ($pred.pI_50$= 5.88) etc. were predicted based on the findings.

• The Korean Journal of Pesticide Science
• /
• v.12 no.1
• /
• pp.18-23
• /
• 2008

3D-QSAR on the inhibitory activities of 6-bromobenzo-[4,5]imidazo[$1,2{\alpha}$]-pyridin-8,9-diones analogues as substrate molecule were studied quantitatively using CoMFA and CoMSIA methods. The statistical values of CoMFA model was better predictability and fitness than CoMSIA model. The inhibitory activities according to the optimized CoMFA 2 model were dependent on the steric field (90.4%). From the CoMFA contour maps, it is found that the branched side chain as R-group will be directly attached to the carbon atom (ipso carbon) of substituent, the inhibitory activities had expected to increase. The positive charge favor groups were placed in the position between imidazol ring and pyridine ring, the inhibitory activities would increase. And if the groups of liner type will be substituted, hydrophilic favor group would raise inhibitory activities.

• Journal of the Society of Cosmetic Scientists of Korea
• /
• v.39 no.4
• /
• pp.329-335
• /
• 2013

Three-dimensional quantitative structure-activity relationships (3D-QSARs) models between the substituents with changing groups ($R_1$ & $R_2$) of 4-hydroxybenzyl alcohol (4-HBA) derivatives as substrate molecule and their inhibitory activities against tyrosinase were derived and discussed quantitatively. The optimized CoMSIA FF model showed the best predictability and fitness ($r^2$ = 0.858 & $q^2$ = 0.951). The contour maps of the optimized CoMSIA FF model showed that, the inhibitory activities of the analogues against tyrosinase were expected to increase when hydrophobic (Hy) favor, negative charge (E) favor, steric (S) disfavor and hydrogen bond donor (HD) disfavor groups were substituted at the $R_2$ position. When the hydrogen bond donor (HD) favor groups were substituted at the $R_1$ position, it is predicted that the substituents will be able to increase the inhibitory activity.

• Bulletin of the Korean Chemical Society
• /
• v.32 no.1
• /
• pp.251-262
• /
• 2011

Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : $r^2$ = 0.955, $q^2$ = 0.781, $r^2_{pred}$ = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.

• KSBB Journal
• /
• v.27 no.2
• /
• pp.121-126
• /
• 2012

In order to explore structural features of minoxidil analogs with a view of enhancing lysyl hydroxylase (LH) inhibitory activity, molecular holographic QSAR (HQSAR) and CoMSIA (comparative molecular similarity indices analysis) were performed. The results from the atomic contributions with optimized the HQSAR 6-2 model indicated that, in case of pyrimidine-1-N-oxide substituent, C2 atom of pyrimidine ring and C'3-C'4 bond of 4-piperidinol group showed the highest impact on the inhibitory activity towards LH enzyme. It was also evident from the information of the optimized CoMSIA F5 model that the inhibitory activity mainly depended on the hydrophobic field contribution (36%) and the hydrogen bond (H-bond) field contribution (49.2%) of substrate molecule. Particularly, it is predicted that the functional groups which disfavor H-bond acceptors in large space around the piperidinol group and also the functional groups which favor the H-bond acceptors at C'4 (& C'5) atom in $R_5$ group play a role for increased inhibitory activity. With this in mind, it is likely that a novel candidate having more improved inhibitory activity on hair growth could be designed in the future.