• Natural Product Sciences
• /
• 제27권2호
• /
• pp.99-114
• /
• 2021

Type 2 diabetes mellitus (T2DM) and its complications are important noncommunicable diseases with high mortality rates. Protein tyrosine phosphatase 1B (PTP1B) and aldose reductase inhibitors are recently approached and advanced for T2DM and its complications therapy. Matricaria chamomilla L. is acknowledged as a worldwide medicinal herb that has many beneficial health effects as well as antidiabetic effects. Our research was designed to determine the most potential antidiabetic phytochemicals from M. chamomilla employing in silico study. 142 phytochemicals were obtained from the databases. The first screening employed iGEMdock and Swiss ADME, involving 93 phytochemicals. Finally, 30 best phytochemicals were docked. Molecular docking and visualization analysis were performed using Avogadro, AutoDock 4.2., and Biovia Discovery Studio 2016. Molecular docking results demonstrate that ligand-protein interaction's binding affinities were -5.16 to -7.54 kcal/mol and -5.30 to -12.10 kcal/mol for PTP1B and aldose reductase protein targets respectively. In silico results demonstrate that M. chamomilla has potential antidiabetic phytochemical compounds for T2DM and its complications. We recommended anthecotulide, quercetin, chlorogenic acid, luteolin, and catechin as antidiabetic agents due to their binding affinities against both PTP1B and aldose reductase protein. Those phytochemicals' significant efficacy and potential as antidiabetic must be investigated in further advanced research.

• Genomics & Informatics
• /
• 제19권1호
• /
• pp.9.1-9.5
• /
• 2021

Mammalian olfactory receptors are a family of G protein-coupled receptors (GPCRs) that occupy a large part of the genome. In human genes, olfactory receptors account for more than 40% of all GPCRs. Several types of GPCR structures have been identified, but there is no single olfactory receptor whose structure has been determined experimentally to date. The aim of this study was to model the interactions between an olfactory receptor and its ligands at the molecular level to provide hints on the binding modes between the OR2W1 olfactory receptor and its agonists and inverse agonists. The results demonstrated the modes of ligand binding in a three-dimensional model of OR2W1 and showed a statistically significant difference in binding affinity to the olfactory receptor between agonists and inverse agonists.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
• /
• pp.180.2-180.2
• /
• 2003

Cathepsin K, a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure-activity studies on a series of azepanone-based diamino and acyclic ketone derivative inhibitors of cathepsin K have led to the design and identification. X-ray structure of the cysteine protease cathepsin K (1NL6) co-crystalized with an inhibitor with 2.8${\AA}$ resolution was used to predict the protein-ligand interactions and to estimate the binding affinity from the docking score by FlexX module. (omitted)

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

• Bulletin of the Korean Chemical Society
• /
• 제33권5호
• /
• pp.1707-1714
• /
• 2012

Grb2 is an adapter protein involved in the signal transduction and cell communication. The Grb2 is responsible for initiation of kinase signaling by Ras activation which leads to the modification in transcription. Ligand based pharmacophore approach was applied to built the suitable pharmacophore model for Grb2. The best pharmacophore model was selected based on the statistical values and then validated by Fischer's randomization method and test set. Hypo1 was selected as a best pharmacophore model based on its statistical values like high cost difference (182.22), lowest RMSD (1.273), and total cost (80.68). It contains four chemical features, one hydrogen bond acceptor (HBA), two hydrophobic (HY), and one ring aromatic (RA). Fischer's randomization results also shows that Hypo1 have a 95% significant level. The correlation coefficient of test set was 0.97 which was close to the training set value (0.94). Thus Hypo1 was used for virtual screening to find the potent inhibitors from various chemical databases. The screened compounds were filtered by Lipinski's rule of five, ADMET and subjected to molecular docking studies. Totally, 11 compounds were selected as a best potent leads from docking studies based on the consensus scoring function and critical interactions with the amino acids in Grb2 active site.

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

• Bulletin of the Korean Chemical Society
• /
• 제31권3호
• /
• pp.606-610
• /
• 2010

Aminoacyl-tRNA synthetases (aaRSs) play vital roles in protein biosynthesis of living organisms and are interesting antibacterial drug targets. In order to find out new inhibitor candidate molecules as antibacterial agent, the binding modes of the candidate molecules were investigated at the active sites of aaRSs by molecular docking study. The docking simulations were performed with 48 compounds from four different scaffolds into the eight different aaRSs. The results show that scaffolds 3 and 4 compounds have consistently better binding capabilities, specifically for HisRS (E. coli) and IleRS (S. aureus). The binding modes of the best compounds with the proteins were well compatible with those of two ligands in crystal structures. Therefore, we expect that the final compounds we present may have reasonable aaRS inhibitory activity.

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

• Molecules and Cells
• /
• 제28권5호
• /
• pp.447-453
• /
• 2009

The quorum sensing (QS) inhibitors that antagonize TraR, a receptor protein for N-3-oxo-octanoyl-L-homoserine lactones (3-oxo-C8-HSL), a QS signal of Agrobacterium tumefaciens were developed. The structural analogues of 3-oxo-C8-HSL were designed by in silico molecular modeling using SYBYL packages, and synthesized by the solid phase organic synthesis (SPOS) method, where the carboxamide bond of 3-oxo-C8-HSL was replaced with a nicotinamide or a sulfonamide bond to make derivatives of N-nicotinyl-L-homoserine lactones or N-sulfonyl-L-homoserine lactones. The in vivo inhibitory activities of these compounds against QS signaling were assayed using reporter systems and compared with the estimated binding energies from the modeling study. This comparison showed fairly good correlation, suggesting that the in silico interpretation of ligand-receptor structures can be a valuable tool for the pre-design of better competitive inhibitors. In addition, these inhibitors also showed anti-biofilm activities against Pseudomonas aeruginosa.

• 생명과학회지
• /
• 제28권2호
• /
• pp.195-200
• /
• 2018

베타아사론은 널리 알려진 석창포의 주요 효능 성분이다. 본 연구에서는 모기의 oviposition 페로몬 성분인 MOP와 석창포 효능성분 베타아사론의 열대집모기 후각 단백질 CquiOBP1 활성 부위에 대한 친화도 분석 실험을 컴퓨터 분자결합 분석 방법을 통해 비교하였다. CquiOBP1 후각 단백질의 3차원 구조 정보는 PDB database (PDB ID: 3OGN)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. CquiOBP1 후각단백질 활성 부위에 대한 베타아사론의 결합친화도는 -6.40 kcal/mol으로 나왔으며 이는 -6.00 kcal/mol으로 나온 MOP의 결합친화도 보다 훨씬 더 높고 효율적인 것으로 분석되었다. 리간드와 상호작용 하는 CquiOBP1단백질 활성 부위의 아미노산들 가운데 TRP114가 공히 MOP와 베타아사론과 결합 하였다. CquiOBP1 단백질 활성부위의 아미노산들을 전혀 다른 전기적 성질을 지닌 아미노산으로 치환 시킨 후 분자결합 분석을 해 본 결과 리간드들의 X,Y,Z Grid 값에 현격한 변화가 유도되었으며 결합 친화도 또한 감소되었다. 이러한 결과를 통하여 베타아사론은 CquiOBP1 단백질 활성을 조절하는 리간드로서 효과적으로 작용할 것으로 보인다. 결론적으로 석창포 추출물 또는 베타아사론은 곤충기피제 신물질 연구 개발 분야에 효율적으로 활용할 수 있을 것으로 사료된다.