CoMFA vs. Topomer CoMFA, which One is better a Case Study with 5-Lipoxygenase Inhibitors

Gadhe, Changdev G. The Basic Science Institute Chosun University 2011 조선자연과학논문집 Vol.4 No.2

Quantitative structure-activity relationships (QSAR) have been applied for two decades in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. The fundamental principle underlying the QSAR is that the structural difference is responsible for the variations in biological activities of the compounds. In this work, we developed 3D-QSAR model for a series of 5-Lipoxygenase inhibitors, utilizing comparative molecular field analysis (CoMFA) and Topomer CoMFA methodologies. Our developed models addressed superiority of Topomer CoMFA over CoMFA. The CoMFA model was obtained with $q^2$=0.593, $r^2$=0.939, $Q^2$=0.334 with 6 optimum number of components (ONC). Higher statistical results were obtained with the Topomer CoMFA model ($q^2$=0.819, $r^2$=0.947, ONC=5). Further robustness of developed models was checked with the ANOVA test and it shows F=113 for CoMFA and F=162.4 for Topomer CoMFA model. Contour map analysis indicated that the more requirement of electrostatic parameter for improved potency.

3β-Hydroxy-12-oleanen-28-oic Acid 유도체들의 PTP-1B 저해활성에 대한 CoMFA 분석과 활성 분자들의 예측

김상진 ( Sang-jin Kim ),김세곤 ( Se-gon Kim ),성낙도 ( Nack-do Sung ) 대한화장품학회 2008 대한화장품학회지 Vol.34 No.2

기질 화합물로써 3β-hydroxy-12-oleanen-28-oic acid 유도체들의 치환기(R₁ ∼ R₄)가 변화함에 따른 protein tyrosine phosphatase (PTP)-1B의 저해활성에 관한 비교 분자장 분석(CoMFA) 모델을 유도하고 정량적으로 검토하였다. 최적의 CoMFA F1 모델은 가장 높은 예측성과 상관성(r²_cv.=0.654 및 r²^ncv.=0.995)을 나타내었다. 저해활성에 관한 CoMFA장 기여비율(%)의 순서는 입체장(53.0 %), 정전기장(36.2 %) 및 소수성장(10.8 %) 이었다. 등고도 분석 결과로부터 저해활성은 기질 분자 내 R₄-치환기에 의존적이었으며 특히 melanin 저해활성이 높은 새로운 화합물(P1 및 P2)이 예측되었다. The comparative molecular field analyses (CoMFA) models between the substituents with changing groups (R₁∼R₄) of 3β-hydroxy-12-oleanen-28-oic acid derivatives as substrate molecule and their inhibitory activities (pI₅₀) against protein tyrosine phosphatase (PTP)-1B were derived and discussed quantitatively. The optimized CoMFA F1 model have best predictability and fitness (r²_cv.=0.654 and r²_ncv.=0.995). The order of contribution ratio (%) with CoMFA fields on the inhibitory activities was a steric field (53.0 %), electrostatic field (36.2 %) and hydrophobic field (10.8 %). From the analytical results of CoMFA contour maps, the inhibitory activities were dependent on the R4 group in substrate molecules. Particularly, the new active compounds (P1 & P2) with the inhibitory activity against melanin synthesis were expected.

생물학적 자극 통제 수단으로 활용하기 위한 돼지 페로몬성 냄새 물질의 탐색 I : Ⅲ. 2-(Cyclohexyloxy) Tetrahydrofurane 유도체와 Porcine Odorant Binding Protein 사이의 결합 친화력에 관한 비교 분자장 분석

성낙도,박창식,정훈성,성민규 충남대학교 형질전환복제돼지연구센터 2007 논문집 Vol. No.10

생물학적 자극통제 수단으로 활용하기 위한 돼지 웅성 페르몬성 분자를 탐색하고자 일련의 냄새 분자로서 2-(cyclo-hexyloxy) tetrahydrofurane 유도체들의 정량적인 구조와 수용체인 porcine odorant binding protein (pOBP)간의 결합 친화력 상수(p(Od)_(50))에 대한 비교 분자장 분석(CoMFA)을 실행하였다. 가장 양호한 CoMFA 모델 ATV (r²_(cv.)(q²)=O.886 및 r²(ncv.)=0.984)은 기질 분자 내 입체 중심(chiral center)의 절대 배열이 C₁(R),C₂(S)인 분자를 atom based fit 방법으로 배열하였을 경우의 standard field와 indicator field가 조합된 CoMFA장의 조건에서 유도되었다. 이 CoMFA 모델은 입체장 40.8%,정전기장 14.6% 및 소수성장 44.6%가 결합 친화력 상수에 영향을 미치는 요소임을 나타내었다. 등고도의 분석 결과로부터 효과적인 결합 친화력 냄새 분자를 수식하는 데 몇 가지 가치 있는 정보를 얻을 수 있었다. To search of new porcine pheromonal odorants for biostirnulation control system technologies to improve reproductive efficiency in livestock species, the comparative molecular field analysis (CoMFA) for binding affinity constant (p(Od)_(50)) between porcine odorant binding protein (pOBP) and ligands of odorant 2-(cyclohexyloxy) tetrahydrofurane derivatives as substrate molecule was conducted and discussed. In the optimized CoMFA model AIV with chirality (C₁'(R), C₂(S)) in substrate molecule and atom based fit alignment (A) of odorants, the statistical results showed the best predictability of the binding affinities (p(Od)_(50)) based on the LOO cross-validated value r²_(cv.) (q²=O.886) and non-cross-validated conventional coefficient (r²_(ncv.)=O.984). The binding affinity constants exhibited a good correlation with steric (40.8%), electrostatic (14.6%) and hydrophobic (44.6%) factors of the substrate molecules. From the analytical results of the contour maps, which may give us some valuable informations to the modification of odorants for effective binding affinity.

생물학적 자극 통제 수단으로 활용하기 위한 돼지 페로몬성 냄새 물질의 탐색: III. 2-(Cyclohexyloxy) Tetrahydrofurane 유도체와 Porcine Odorant Binding Protein 사이의 결합 친화력에 관한 비교 분자장 분석

성낙도,박창식,정훈성,성민규 한국동물생명공학회(구 한국동물번식학회) 2006 Reproductive & developmental biology Vol.30 No.1

생물학적 자극통제 수단으로 활용하기 위한 돼지 웅성 페르몬성 분자를 탐색하고자 일련의 냄새 분자로서 2-(cyclo-hexyloxy) tetrahydrofurane 유도체들의 정량적인 구조와 수용체인 porcine odorant binding protein (pOBP)간의 결합 친화력 상수(p(Od)50)에 대한 비교 분자장 분석(CoMFA)을 실행하였다. 가장 양호한 CoMFA 모델 AIV (r2 cv.(q2)=0.886 및 r2 ncv.=0.984)은 기질 분자 내 입체 중심(chiral center)의 절대 배열이 C1(R),C2(S)인 분자를 atom based fit 방법으로 배열하였을 경우의 standard field와 indicator field가 조합된 CoMFA장의 조건에서 유도되었다. 이 CoMFA 모델은 입체장 40.8% 정전기장 14.6%및 소수성장 44.6%가 결합 친화력 상수에 영향을 미치는 요소임을 나타내었다. 등고도의 분석 결과로부터 효과적인 결합 친화력 냄새 분자를 수식하는 데 몇 가지 가치 있는 정보를 얻을 수 있었다. To search of new porcine pheromonal odorants for biostimulation control system technologies to improve reproductive efficiency in livestock species, the comparative molecular field analysis (CoMFA) for binding affinity constant (p(Od)50) between porcine odorant binding protein (pOBP) and ligands of odorant 2-(cyclohexyloxy) tetrahydrofurane derivatives as substrate molecule was conducted and discussed. In the optimized CoMFA model AIV with chirality (C1'(R), C2(S)) in substrate molecule and atom based fit alignment (A) of odorants, the statistical results showed the best predictability of the binding affinities (p(Od)50) based on the LOO cross-validated value r2 cv.(q2=0.886) and non-cross-validated conventional coefficient (r2 ncv.=0.984). the binding affinity constants exhibited a good correlation with steric (40.8%), electrostatic (14.6%) and hydrophobic (44.6%) factors of the substrate molecules. from the analytical results of the contour maps, which may give us some valuable informations to the modification of odorants for effective binding affinity.

생물학적 자극 통제 수단으로 활용하기 위한 돼지 페로몬성 냄새 물질의 탐색 3 : 2-(Cyclohexyloxy) Tetrahydrofurane 유도체와 Porcine Odorant Binding Protein 사이의 결합 친화력에 관한 비교 분자장 분석

성낙도,박창식,정훈성,성민규 한국동물번식학회 2006 Reproductive & developmental biology Vol.30 No.1

생물학적 자극통제 수단으로 활용하기 위한 돼지 웅성 페르몬성 분자를 탐색하고자 일련의 냄새 분자로서 2-(cyclo-hexyloxy) tetrahydrofurane 유도체들의 정량적인 구조와 수용체인 porcine odorant binding protein (pOBP)간의 결합 친화력 상수(p(Od)50)에 대한 비교 분자장 분석(CoMFA)을 실행하였다. 가장 양호한 CoMFA 모델 AIV (r2 cv.(q2)=0.886 및 r2 ncv.=0.984)은 기질 분자 내 입체 중심(chiral center)의 절대 배열이 C1(R),C2(S)인 분자를 atom based fit 방법으로 배열하였을 경우의 standard field와 indicator field가 조합된 CoMFA장의 조건에서 유도되었다. 이 CoMFA 모델은 입체장 40.8% 정전기장 14.6%및 소수성장 44.6%가 결합 친화력 상수에 영향을 미치는 요소임을 나타내었다. 등고도의 분석 결과로부터 효과적인 결합 친화력 냄새 분자를 수식하는 데 몇 가지 가치 있는 정보를 얻을 수 있었다. To search of new porcine pheromonal odorants for biostimulation control system technologies to improve reproductive efficiency in livestock species, the comparative molecular field analysis (CoMFA) for binding affinity constant (p(Od)50) between porcine odorant binding protein (pOBP) and ligands of odorant 2-(cyclohexyloxy) tetrahydrofurane derivatives as substrate molecule was conducted and discussed. In the optimized CoMFA model AIV with chirality (C1'(R), C2(S)) in substrate molecule and atom based fit alignment (A) of odorants, the statistical results showed the best predictability of the binding affinities (p(Od)50) based on the LOO cross-validated value r2 cv.(q2=0.886) and non-cross-validated conventional coefficient (r2 ncv.=0.984). the binding affinity constants exhibited a good correlation with steric (40.8%), electrostatic (14.6%) and hydrophobic (44.6%) factors of the substrate molecules. from the analytical results of the contour maps, which may give us some valuable informations to the modification of odorants for effective binding affinity.

3D-QSAR Studies of 2-Arylbenzoxazoles as Novel Cholesteryl Ester Transfer Protein Inhibitors

Jahan B. Ghasemi,Mahnaz Ayati,Somayeh Pirhadi 대한화학회 2011 Bulletin of the Korean Chemical Society Vol.32 No.2

The 3D-QSAR study of 2-arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors was performed by comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RF) for optimizing the region for the final PLS analysis, and comparative molecular similarity indices analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The best orientation was searched by all-orientation search strategy using AOS, to minimize the effect of the initial orientation of the structures. The predictive ability of CoMFARF and CoMSIA were determined using a test set of twelve compounds giving predictive correlation coefficients of 0.886, and 0.754 respectively indicating good predictive power. Further, the robustness and sensitivity to chance correlation of the models were verified by bootstrapping and progressive scrambling analyses respectively. Based upon the information derived from CoMFA(RF) and CoMSIA, identified some key features that may be used to design new inhibitors for cholesteryl ester transfer protein.

3D-QSAR Studies of 2-Arylbenzoxazoles as Novel Cholesteryl Ester Transfer Protein Inhibitors

Ghasemi, Jahan B.,Pirhadi, Somayeh,Ayati, Mahnaz Korean Chemical Society 2011 Bulletin of the Korean Chemical Society Vol.32 No.2

The 3D-QSAR study of 2-arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors was performed by comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RF) for optimizing the region for the final PLS analysis, and comparative molecular similarity indices analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The best orientation was searched by all-orientation search strategy using AOS, to minimize the effect of the initial orientation of the structures. The predictive ability of CoMFARF and CoMSIA were determined using a test set of twelve compounds giving predictive correlation coefficients of 0.886, and 0.754 respectively indicating good predictive power. Further, the robustness and sensitivity to chance correlation of the models were verified by bootstrapping and progressive scrambling analyses respectively. Based upon the information derived from CoMFA(RF) and CoMSIA, identified some key features that may be used to design new inhibitors for cholesteryl ester transfer protein.

Prediction on the Chiral Behaviors of Drugs with Amine Moiety on the Chiral Cellobiohydrolase Stationary Phase Using a Partial Least Square Method

Choi, Sun-Ok,Lee, Seok-Ho,Park Choo , Hea-Young The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.10

Quantitative Structure-Resolution Relationship (QSRR) using the Comparative Molecular Field Analysis (CoMFA) software was applied to predict the chromatographic behaviors of chiral drugs with an amine moiety on the chiral cellobiohydrolase (CBH) columns. As a result of the Quantitative CoMFA-Resolution Relationship study, using the partial least square method, prediction of the behavior of drugs with amine moiety upon chiral separation became possible from their three dimensional molecular structures. When a mixed mobile phase of 10 mM aqueous phosphate buffer (pH 7.0) - isopropanol (95 : 5) was employed, the best Quantitative CoMFA-Resolution Relationship, derived from the study, provided a cross-validated $q^2$ = 0.933, a normal $r^2$ = 0.995, while the best Quantitative CoMFA-Separation Factor Relationship, also derived from the study, yielded a cross-validated $q^2$ = 0.939, a normal $r^2$ = 0.991. When all of these results are considered, this QSRR-CoMFA analysis appears to be a very useful tool for the preliminary prediction on the chromatographic behaviors of drugs with an amine moiety inside chiral CBH columns.

QSAR Analyses on the Cell Cytotoxicity of Some N-phenyl-O-phenylthionocarbamate Derivatives Using Comparative Molecular Field Analysis (CoMFA) Based on Different Alignment Approaches and Holographic Quantitative Structure-Activity Relationship(HQSAR)

Song, Nack-Do,Myung, Pyung-Keun,Seong, Min-Gyu,Yu, Seong-Jae,Choi, Su-La 충남대학교 형질전환복제돼지연구센터 2004 논문집 Vol. No.8

A series of 22 new N-phenyl-O-(4-methoxyphenyl)thionocarbamate derivatives were synthesized and examined in vitro for cytotoxicity on human skin cancer cell line, SK-MEL-28 cells, by MTT assay. 3D-QSAR/CoMFA and HQSARmodels were developed to guide the rational design of novel analogs exhibiting improved biological property. Two models exhibiting excellent self-consistency(r²>0.90) and predictability(q²>0.50) were developed. For alignment, atom fit(r²=0.985 & q²=.526) and field fit (r²=0.996 & q²=0.495) were applied to compare the predictability of each model in CoMFA. Quality of HQSAR(r²=0.967 & q²=0.807) was slightly higher than that of CoMFA in terms of cross-validated predictive correlation coefficient, q² values, but showed relatively poor predictability. Cytotoxicity(pI_50) against SK-MEL-28 cells, based on CoMFA analysis results, exhibited a good correlation.Reliable results could be obtained using the two models for prediction in vitro cytotoxicity (pI_50) against SK-MEL-28 cells of thionocabamate derivatives.

CoMFA 법을 이용한 3-아릴이소퀴놀린 화합물들의 SK-OV-3 암세포에 대한 가상의 약물 작용 수용체 해석

김의기,민선영,정병호,천승훈,최보길,조원제 전남대학교 약품개발연구소 2002 약품개발연구지 Vol.11 No.-

We have performed a 3D-QSAR/ CoMFA analysis of the cytotoxiv activities of thirty-five 3-arylisoquinoline derivative against SK-OV-3 tumor cell line. The results suggested that the electrostatic, steric and hydrophobic factors of 3-arylisoquinoline were strongly correlated with the antitumor activity. Considerable predictive ability (cross-validated r2 as high as 0.841) was obtained through CoMFA.