• 약학회지
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• 제55권2호
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• pp.98-105
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• 2011

To search the minimum structural requirement of tricyclic isoxazole analogues (1~30) as new class potent antidepressant, thee-dimensional quanti- tative-structure relationship (3D-QSAR) models between substituents ($R_1{\sim}R_5$) of tricyclic isoxazoles and their antidepressant activity against medetomidine-induced loss of righting were performed and discussed quantitatively using comparative molecular field analysis (CoMFA) and comparative molecular similarity indies analysis (CoMSIA) methods. The correlativity and predictability ($r^2$=0.484 and $q^2$=0.947) of CoMSIA-2 model were higher than those of the rest models. The inhibitory activity against medetomidine-induced loss of righting was dependent on electrostatic field (43.4%), hydrophobic field (35.3%), and steric field (21.2%) of tricyclic isoxazoles. From the CoMSIA-2 contour maps, it is predicted that the antidepressant activity of potent antidepressants against medetomidine-induced loss of righting will be able to increase by the substituents ($R_1{\sim}R_5$) which were in accord with CoMSIA field.

• Bulletin of the Korean Chemical Society
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• 제34권6호
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• pp.1823-1828
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• 2013

Tetraoxanes (1,2,4,5-tetraoxanes) have been reported to exhibit potent antimalarial activity. In the present study, the three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of tetraoxanes derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best predictive CoMFA model with atom fit alignment resulted in cross-validated coefficient ($q^2$) value of 0.719, non-cross-validated coefficient ($r^2$) value of 0.855 with standard error of estimate (SEE) 0.335. Similarly, the best predictive CoMSIA model was derived with $q^2$ of 0.739, $r^2$ of 0.847 and SEE of 0.344. The generated models were externally validated using test sets. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel tetraoxanes having improved antimalarial activity.

• Bulletin of the Korean Chemical Society
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• 제26권6호
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• pp.952-958
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• 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.

• 통합자연과학논문집
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• 제9권1호
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• pp.1-9
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• 2016

Leucine rich repeat kinase 2 (LRRK2) is a highly promising target for Parkinson's disease (PD) that affects millions of people worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of pyrrolopyrimidine-based selective LRRK2 kinase inhibitors. This study was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. A reliable 3D-QSAR model was developed using comparative molecular field analysis (CoMFA) technique. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.539 and a non-cross-validated correlation coefficient ($r^2$) of 0.871. Robustness of the model was further evaluated by bootstrapping and progressive scrambling analysis. This work could assist in designing more potent LRRK2 inhibitors.

• 통합자연과학논문집
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• 제4권4호
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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.

• 통합자연과학논문집
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• 제8권3호
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• pp.176-183
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• 2015

Corticotropin-releasing actor receptors (CRFRs) activates the hypothalamic pituitary adrenal axis, one of the 2 parts of the fight or flight response to stress. Increased CRH production has is associated with Alzheimer's disease and major depression and hypoglycemia. In this study, we report the important structural and chemical parameters for CRFR inhibitors using the derivatives of 8-substituted-2-aryl-5-alkylaminoquinolines. A 3D QSAR study, Comparative molecular field analysis (CoMFA) was performed. The best predictions were obtained for the best CoMFA model with a $q^2$ of 0.607 with 6 components and $r^2$ of 0.991. The statistical parameters from the generated CoMFA models indicated that the data are well fitted and have high predictive ability. The contour map resulted from the CoMFA models might be helpful in the future designing of novel and more potent CRFR derivatives.

• 분석과학
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• 제24권6호
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• pp.533-543
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• 2011

hERG (human ether-a-go-go related gene) 이온채널은 심장 재분극의 중요 요소이며 이 채널의 저해제는 부정맥과 돌연사를 유발할 수 있다. 따라서, 신약개발과정에서 후보물질이 hERG 이온채널의 잠재적인 저해제일 경우에는 심장독성 부작용을 유발하므로, 이를 최소화하고자 많은 노력이 집중되고 있다. 본 연구는 HEK(인간 배아 신장)세포에서 얻은 202개 유기화합물의 $IC_{50}$ 데이터를 이용하여 2차원 구조-활성의 정량적 관계(2D-QSAR)방법으로 예측하는 모델을 개발하였다. hERG이온채널 저해제의 기계 학습방법으로는 다중선형회귀(Multiple Linear Regression), 서포트 벡터 머신(Support Vector Machine: SVM)방법과 인공신경망(Artificial Neural Network)방법이며, 교차검증을 적용한 모집단 기반 전진선택(forward selection)방법과 결합하여 각 학습모델에 적합한 최적의 표현자들을 결정하였다. 가장 우수한 방법은 14종의 표현자를 사용한 인공신경망방법($R^2_{CV}$=0.617, RMSECV=0.762, MAECV=0.583)이었고, 다중선형회귀방법을 통해서 hERG이온채널 저해물질의 구조적 특징과 수용체와의 상호작용을 설명할 수 있다. QSAR모델의 검증은 교차검증과 Y-scrambling test방법으로 수행하였다.

• 농약과학회지
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• 제2권2호
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• pp.16-21
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• 1998

비스 방향족 ${\alpha},{\beta}$-불포화 케톤 유도체의 헤테로 방향족고리($R_{1}$) 치환체중 치환 phenyl backbone($R_{2}$)들의 구조변환에 따른 벼도열병균(Pyricularia oryzae)과 토마토역병균(Phytophthora irifestans)에 대한 in vivo에서의 항균활성 관계(SAR)를 3-D QSAR 방법인 비교분자장 분석(CoMFA)으로 해석하였다. 두 식물병원균에 대한 항균활성을 설명하는 CoMFA결과는 2-D QSAR에서 검토된 결과와 유사한 경향이었으며 입체효과(Es)와 전자효과(${\sigma}$)로 설명할 수 있었다. 즉, 벼도열병균은 aryl group에 bulky한 치환기(Es>0)가 도입되어야 하며 ${\beta}$탄소원자의 양하전이 증가할수록 강한 항균활성을 나타낼것으로 기대되었다. 반면, 토마토역병균의 경우에는 aryl group에 체적이 작은 치환기가 도입될수록, 그리고 ${\beta}$ 탄소원자의 양하전이 감소할수록 강한 항균활성을 나타낼 것으로 기대 되었다. 또한, 입체효과와 전자효과를 등 고도로 나타낸 CoMFA결과가 기존의 2-D QSAR보다 항균활성에 미치는 화합물의 구조적 요인을 보다 구체적으로 제시할 수 있었다.

• 통합자연과학논문집
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• 제8권3호
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• pp.214-220
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• 2015

Cancer has emerged as one of the leading cause of deaths worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of quinazoline-based anticancer agents. Purpose of the study is to understand the structural basis for their inhibitory activity. Comparative molecular field analysis (CoMFA) technique was employed to develop 3D-QSAR model. Ligand-based alignment scheme was used to generate a reliable CoMFA model. The model produced statistically significant results with a cross-validated correlation coefficient ($q^2$) of 0.589 and a non-cross-validated correlation coefficient ($r^2$) of 0.928. Model was further validated by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel and more potent anticancer agents.

• 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.