• 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.

• 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.

• 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.

• 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.

• KSBB Journal
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• 제15권3호
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• pp.299-306
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• 2000

발광미생물 (luminescent bacteria)인 P. phosphoreum을 이용한 수계의 환경독성물질로 지정된 ethane, benzene, phenol류에 chlorine이 치환된 l47~의 독성강도를 생체발광의 50%저하시키 는 독성농도인 ECso값을 통한 생물학적 정량을 하였을 때 phenol) benzene) ethane 의 순서로 독성깅도가 높게 산출되 어졌으며, 특히 지환된 chlo괴ne의 수가 증가할수록 독성강도가 강하다는 것을 알 수 있었다. 또한 산출된 ECso값을 이용허여 독성물질들의 물려화학적 parameter특성인 octan이(water 분할계 수 (log P), 용해도 (log S) 및 solvatochromic parameter의 떤관쟁 을 QSAR 모탤링하였으며 실힘을 통하지 않고, 독성의 독성강도 를 예측할 수 있는 회기식을 다음과 같이 산출하였다. $log EC_{50} =2.48 + 0.914 log S(n=9 R2=85.5% RE=0.378) log EC_{50}=0.35 - 4.48 Vi/100 + 2.84 \pi^* +9.46{\beta}m-4.48am (n =14 R2=98.2% RE=0.012) log EC_{50} =2.64 -1.66 log P(n=5, R2=98.8% RE=0.16) log EC_{50}=3.44 -1.09 log P(n=9 R2= 80.8% Re=0.207)$. QSAR 모델은 QSAR 검증식을 통하여 확인된 다중회기식을 이용함으로 실험하지 않은 독성물 질이 갖는 물리화학적인 특성을 대입하여 log Eeso값을 예측할 수 있으므로 경제적, 시간적으로 이익을 얻을 수 있는 모델이다.

• 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.

• Genomics & Informatics
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• 제5권1호
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• pp.24-29
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• 2007

Computational virtual screening has become an essential platform of drug discovery for the efficient identification of active candidates. Moleculardocking, a key technology of receptor-centric virtual screening, is commonly used to predict the binding affinities of chemical compounds on target receptors. Despite the advancement and extensive application of these methods, substantial improvement is still required to increase their accuracy and time-efficiency. Here, we evaluate several advanced structure-based virtual screening approaches for elucidating the rank-order activity of chemical libraries, and the quantitative structureactivity relationship (QSAR). Our results show that the ensemble-average free energy estimation, including implicit solvation energy terms, significantly improves the hit enrichment of the virtual screening. We also demonstrate that the assignment of quantum mechanical-polarized (QM-polarized) partial charges to docked ligands contributes to the reproduction of the crystal pose of ligands in the docking and scoring procedure.

• Korean Chemical Engineering Research
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• 제61권4호
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• pp.523-541
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• 2023

3D 프린터의 활용이 높아짐에 따라 발생하는 화학물질에 대한 노출 빈도가 증가하고 있다. 그러나 3D 프린팅 발생 화학물질의 독성 및 유해성에 대한 연구는 미비하며, 분자 구조 데이터의 결측치로 인해 in silico 기법을 사용한 독성예측 연구는 저조한 실정이다. 본 연구에서는 화학물질의 분자구조 정보를 나타내는 주요 분자표현자의 결측치를 보간하여 3D 프린팅의 독성 및 유해성을 예측한 Data-centric QSAR 모델을 개발하였다. 먼저 MissForest 알고리즘을 사용해 3D 프린팅으로 발생되는 유해물질의 분자표현자 결측치를 보완하였으며, 서로 다른 4가지 기계학습 모델(결정트리, 랜덤포레스트, XGBoost, SVM)을 기반으로 Data-centric QSAR 모델을 개발하여 생물 농축 계수(Log BCF)와 옥탄올-공기분배계수(Log Koa), 분배계수(Log P)를 예측하였다. 또한, 설명 가능한 인공지능(XAI) 방법론 중 TreeSHAP (SHapley Additive exPlanations) 기법을 활용하여 Data-centric QSAR 모델의 신뢰성을 입증하였다. MissForest 알고리즘 기반 결측지 보간 기법은, 기존 분자구조 데이터에 비하여 약 2.5배 많은 분자구조 데이터를 확보할 수 있었다. 이를 바탕으로 개발된 Data-centric QSAR 모델의 성능은 Log BCF, Log Koa와 Log P를 각각 73%, 76%, 92% 의 예측 성능으로 예측할 수 있었다. 마지막으로 Tree-SHAP 분석결과 개발된 Data-centric QSAR 모델은 각 독성치와 물리적으로 상관성이 높은 분자표현자를 통하여 선택함을 설명할 수 있었고 독성 정보에 대한 높은 예측 성능을 확보할 수 있었다. 본 연구에서 개발한 방법론은 다른 프린팅 소재나 화학공정, 그리고 반도체/디스플레이 공정에서 발생 가능한 오염물질의 독성 및 인체 위해성 평가에 활용될 수 있을 것으로 사료된다.

• 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.