• Bulletin of the Korean Chemical Society
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• 제35권8호
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• pp.2494-2504
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• 2014

P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

• Genomics & Informatics
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• 제14권3호
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• pp.96-103
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• 2016

The influenza A (H1N1) virus, also known as swine flu is a leading cause of morbidity and mortality since 2009. There is a need to explore novel anti-viral drugs for overcoming the epidemics. Traditionally, different plant extracts of garlic, ginger, kalmegh, ajwain, green tea, turmeric, menthe, tulsi, etc. have been used as hopeful source of prevention and treatment of human influenza. The H1N1 virus contains an important glycoprotein, known as neuraminidase (NA) that is mainly responsible for initiation of viral infection and is essential for the life cycle of H1N1. It is responsible for sialic acid cleavage from glycans of the infected cell. We employed amino acid sequence of H1N1 NA to predict the tertiary structure using Phyre2 server and validated using ProCheck, ProSA, ProQ, and ERRAT server. Further, the modelled structure was docked with thirteen natural compounds of plant origin using AutoDock4.2. Most of the natural compounds showed effective inhibitory activity against H1N1 NA in binding condition. This study also highlights interaction of these natural inhibitors with amino residues of NA protein. Furthermore, among 13 natural compounds, theaflavin, found in green tea, was observed to inhibit H1N1 NA proteins strongly supported by lowest docking energy. Hence, it may be of interest to consider theaflavin for further in vitro and in vivo evaluation.

• 한국자기공명학회논문지
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• 제15권1호
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• pp.80-89
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• 2011

3D structures of STAM1 UIM-ubiquitin complex were presented to predict and analyze the interaction between UIM and ubiquitin. To generate the protein-peptide complex structure, the RosettaDock method was used with and without NMR restraints. High resolution complex structure was acquired successfully and evaluated electrostatic interaction in the protein-peptide binding with several charged residues at the binding site. From docking results, the Rosettadock method could be useful to acquire essential information of protein-protein or protein-peptide interaction with minimal biological evidences.

• 통합자연과학논문집
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• 제11권1호
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• pp.9-13
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• 2018

KiSS1-derived peptide receptor, a GPCR protein, binds with the hormone Kisspeptin plays a major role in the neuroendocrine regulation of reproduction. It is important in the onset of puberty and triggers the release of gonadotrophin-releasing hormone. It is a potential drug target for the disorders related to GnRH, hence, analysing the structural features of the receptor becomes important. The three dimensional of the receptor modelled in a previous study was utilised. In this study, we have analysed the protein - protein interaction of the receptor with Kisspeptin 10 and 15. The study revealed the important residues which are involved in the interaction. The result of this study could be helpful in understanding the mechanism of Kiss1 receptor activation and the pathophysiology of the disorders related to the receptor.

• 생명과학회지
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• 제28권4호
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• pp.408-414
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• 2018

Actein은 널리 알려진 승마 추출물의 주요 생리 활성 효능 성분이다. 본 연구에서는 acetylcholine 수용체의 활성을 억제하는 것으로 활용된 AchBP 단백질 길항제(antagonist) tubocurarine과 승마 추출물의 효능 성분 actein 및 actein 유도체(27-deoxyactin, (26S)-actein, (26R)-actein)들의 AchBP 단백질 B와 C domain 활성 부위에 대한 친화도 분석 실험을 컴퓨터 분자결합 분석 방법을 통해 비교하였다. AchBP 단백질 B와 C domain의 3차원 구조정보는 PDB database (PDB ID: 2XYT)를 활용하였다. In silico 결합 분석을 수행하기 위해 PyRx, Autodock Vina, Discovery Studio Version 4.5, and NX-QuickPharm 프로그램을 각 분석 조건에 따라 활용하였다. AchBP 단백질 B와 C domain 활성 부위에 대한 actein의 최대 결합친화도는 -10.50 kcal/mol으로 나왔으며 이는 -9.80 kcal/mol으로 분석된 tubocurarine의 결합 친화도 보다 훨씬 더 높고 효율적인 것으로 분석되었다. Tubocurarine에 비하여 결합친화도 값이 높게 분석된actein, 27-deoxyactein, (26R)-actein 유도체 성분들과 상호작용 하는 AchBP 단백질 활성 부위의 아미노산들 가운데 tryptophan 84와 tyrosine 147이 높은 결합친화도를 형성하는데 매우 중요한 역할을 하는 아미노산으로 예상이 되었다. Tubocurarine의 AchBP 단백질 활성 부위에 대한 X,Y,Z Grid 값은 X=38.300689, Y=112.053467, Z=51.991022으로 나왔으나 actein과 actein 유도체들은 대부분 X=26.4, Y=127.3, Z=43.7 값 주변에 centroid grid를 형성하였다. 즉, tubocurarine이 결합하는 부위와는 다른 부위에 결합하여 AchBP의 활성에 영향을 주는 것으로 사료되었다. 이상의 연구 결과들을 분석해 볼 때, 아세틸콜린 수용체 길항제 tubocurarine보다 승마 추출물 생리 활성 물질인 actein과 그 유도체들이 보다 더 효율적인 아세틸콜린 수용체 길항제로 작용할 수 있음을 확인하였다. 결론적으로 승마 추출물 또는 actein 성분은 피부 주름 개선 효능을 지닌 보톡스를 대체하거나 또는 주름 개선용 화장품 신물질 연구 개발 분야에 효율적으로 활용할 수 있을 것으로 사료된다.

• Journal of Ginseng Research
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• 제46권6호
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• pp.750-758
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• 2022

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI. Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a proteineprotein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking. Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I. Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

• 한국환경보건학회지
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• 제38권4호
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• pp.351-359
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• 2012

Objectives: This study was conducted in order to investigate the specific correlation between physicochemical properties and bioactivity in ecdysteroids found in living organisms. Methods: The examined steroidal compounds were classified into three groups according to their relevance to ecdysone activity. Each compound molecule was completely drawn to automatically calculate its physicochemical parameters and docked against 20-hydroxyecdysone to calculate the total distance. Electronic charge distribution was also observed for each molecule. All procedures were conducted using a computational chemistry program. Results: Ecdysone agonists showed different ranges of parameter values, such as log P, hydrophilic-lipophilic balance (HLB), solubility parameter (SP), hydrophilic surface (HPS), hydrogen bond (HB) and Kappa 2, when compared with antagonists and steroids without ecdysone activity. They also showed a similar electronic charge distribution that is significantly different from the electron charge distribution of antagonists and steroids without ecdysone activity. The total distance values of agonists, estimated by docking them with 20-hydroxyecdysone, were relatively small but showed no correlation with binding affinity with receptor ligand. Conclusions: These results suggest that physicochemical properties such as steric and electronic effects, hydrophobicity and hydrogen bonding may operate in combination to determine the binding activity of ecdysteroids to the receptor protein.

• EDISON SW 활용 경진대회 논문집
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• 제2회(2013년)
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• pp.89-100
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• 2013

생물정보학의 다양한 이론적 내용과 계산적 방법들이 갈수록 전문화 되어짐에 따라 신약 개발, 신 물질 합성, 단백질의 구조 예측 등 다양한 분야에서 필요성이 커져가고 있다. 이 중 molecular docking 기술은 단백질과 특정 분자간의 결합 형태를 분자 모델링 기법을 통해 알아내는 방법이며 신약개발 연구에 큰 영향을 미치고 있다. Molecular docking을 통하여 분자간의 결합 형태를 예측하는 과정에서 Protein-ligand complex의 정확한 에너지 측정을 가능하게 하는 scoring function이 필요하다. 그런데 본 연구에서 사용한 B-Raf kinase protein 은 active site 부분에서 ligand와 receptor 간에 aromatic ring로 인한 ${\pi}-{\pi}$ interaction이 정확한 에너지 계산을 어렵게 한다. 이러한 ${\pi}-{\pi}$ interaction 부분의 에너지를 정확하게 계산하기 위해 양자역학 계산을 실시하였다. Active site 부분에서 ligand와 receptor에서 발생하는 각각 다른 5개의 ${\pi}-{\pi}$ interaction 구조를 준비하여 Gaussian을 통해 양자역학 에너지를 계산하였다. 그리고 이러한 결과 값들이 ligand의 활성 값과 어떤 상관관계를 갖는지 살펴보았다. 그 결과 ${\pi}-{\pi}$ interaction을 양자역학으로 계산한 값이 그렇지 않은 것보다 더 좋은 상관관계를 보여주었다. 이는 특별한 구조의 영향으로 ligand와 receptor 간의 결합에너지를 정확하게 계산하기 어려운 문제에서 양자역학을 적용할 경우 더욱 좋은 결과값을 얻을 수 있었다. 또한 이러한 데이터가 신 물질 개발이나 신약 개발 등의 다양한 분야에서 계산화학 방법이 신뢰성을 얻는데 도움 될 수 있다고 생각된다.

• Bulletin of the Korean Chemical Society
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• 제29권5호
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• pp.921-927
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• 2008

Discovery of $\alpha$-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate mediated diseases. As a method for the discovery of new novel inhibitors of $\alpha$-glucosidase, we have addressed the performance of the computer-aided drug design protocol involving the homology modeling of $\alpha$-glucosidase and the structure-based virtual screening with the two docking tools: FlexX and the automated and improved AutoDock implementing the effects of ligand solvation in the scoring function. The homology modeling of $\alpha$-glucosidase from baker’s yeast provides a high-quality 3-D structure enabling the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands to the extent of 5-fold enhancement of hit rate in database screening when 1% of database coverage is used as a cutoff. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of $\alpha$- glucosidase through the simultaneous establishment of the multiple hydrogen bond and hydrophobic interactions. The present study demonstrates the usefulness of the automated AutoDock program with the improved scoring function as a docking tool for virtual screening of new $\alpha$-glucosidase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.

• Journal of Ginseng Research
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• 제47권2호
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• pp.228-236
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• 2023

Background: QiShen YiQi pills (QSYQ) is a Traditional Chinese Medicine (TCM) formula, which has a significant effect on the treatment of patients with myocardial infarction (MI) in clinical practice. However, the molecular mechanism of QSYQ regulation pyroptosis after MI is still not fully known. Hence, this study was designed to reveal the mechanism of the active ingredient in QSYQ. Methods: Integrated approach of network pharmacology and molecular docking, were conducted to screen active components and corresponding common target genes of QSYQ in intervening pyroptosis after MI. Subsequently, STRING and Cytoscape were applied to construct a PPI network, and obtain candidate active compounds. Molecular docking was performed to verify the binding ability of candidate components to pyroptosis proteins and oxygen-glucose deprivation (OGD) induced cardiomyocytes injuries were applied to explore the protective effect and mechanism of the candidate drug. Results: Two drug-likeness compounds were preliminarily selected, and the binding capacity between Ginsenoside Rh2 (Rh2) and key target High Mobility Group Box 1 (HMGB1)was validated in the form of hydrogen bonding. 2 μM Rh2 prevented OGD-induced H9c2 death and reduced IL-18 and IL-1β levels, possibly by decreasing the activation of the NLRP3 inflammasome, inhibiting the expression of p12-caspase1, and attenuating the level of pyroptosis executive protein GSDMD-N. Conclusions: We propose that Rh2 of QSYQ can protect myocardial cells partially by ameliorating pyroptosis, which seems to have a new insight regarding the therapeutic potential for MI.