• 통합자연과학논문집
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• 제5권1호
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• pp.22-26
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• 2012

Chemokine receptor antagonists have potential applications in field of drug discovery. Although the chemokine receptors are G-protein-coupled receptors, their cognate ligands are small proteins (8 to 12 kDa), and so inhibiting the ligand/receptor interaction has been challenging. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, targeting both CCR2 and CCR5 could be a useful strategy. Because of the importance of these receptors, providing information regarding the binding site is of prime importance. Herein, we report the comparison of CCR2 of CCR5 binding sites both sequentially as well as structurally. We also urged the importance of crucial residues in the binding site, to facilitate the development of dual antagonists targeting both the receptors. These results could also be useful for the design of novel and potent dual CCR2 and CCR5 antagonists using structure based drug design.

• 통합자연과학논문집
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• 제4권3호
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• pp.202-209
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• 2011

Tuberculosis is a major health problem in humans because of its multidrug resistance and discovering new treatments for this disease is urgently required. The synthesis of isoprenoids in Mycobacterium tuberculosis has been reported as an interesting pathway to target. In this context, 2C-methyl-D-erythritol 4-phosphate (MEP) pathway of M. tuberculosis has drawn attention. The MEP pathway begins with the condensation of glyceraldehyde 3-phosphate and pyruvate forming 1-deoxy-D-xylulose 5-phosphate (DXP) which is catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS). As there is no X-ray structure was reported for this target, comparative modeling was used to generate the three dimensional structure. The structure was further validated by PROCHECK, VERIFY-3D, PROSA, ERRAT and WHATIF. Molecular docking studies was performed with the substrate (Thiamine pyrophosphate) and the reported inhibitor 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolol[1,5-a]pyrimidin-7-one) against the developed model to identify the crucial residues in the active site. This study may further be useful to provide structure based drug design.

• 한국생물정보학회:학술대회논문집
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• 한국생물정보시스템생물학회 2005년도 BIOINFO 2005
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• pp.139-143
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• 2005

Cytochrome P450 14${\alpha}$-sterol demethylase enzyme (CYP51) is the target a of azole type antifungals. The azole blocks the ergosterol synthesis and thereby inhibits fungal growth. A three-dimensional (3D) homology model of CYP51 from Candida albicans was constructed based on the X-ray crystal structure of CYP51 from Mycobacterium tuberculosis. Using this model, the binding modes for the substrate (24-methylene-24, 25-dihydrolanosterol) and the known inhibitors (fluconazole, voriconazole, oxiconazole, miconazole) were predicted from docking. Virtual screening was performed employing Structure Based Focusing (SBF). In this procedure, the pharmacophore models for database search were generated from the protein-ligands interactions each other. The initial structure-based virtual screening selected 15 compounds from a commercial available 3D database of approximately 50,000 molecule library, Being evaluated by a cell-based assay, 5 compounds were further identified as the potent inhibitors of Candida albicans CYP51 (CACYP51) with low minimal inhibitory concentration (MIC) range. BMD-09-01${\sim}$BMD-09-04 MIC range was 0.5 ${\mu}$g/ml and BMD-09-05 was 1 ${\mu}$g/ml. These new inhibitors provide a basis for some non-azole antifungal rational design of new, and more efficacious antifungal agents.

• Bulletin of the Korean Chemical Society
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• 제28권2호
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• pp.211-219
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• 2007

The subtle but significant differences and thereby the lack of consensus in active site structures among the crystal structures of cyclin-dependent kinase 2 (CDK2) has hampered structure-based drug design. In this study, we devised a simple but effective ‘mutation, pharmacophore-guided docking, followed by mutation' strategy to generate an “average” CDK2 structure, which was used for ligand docking study to successfully reproduce 30 out of 32 X-ray ligand positions within 2.0 A of heavy atom RMSD. This novel docking method was applied for structure-based 3D QSAR with CoMSIA study of a series of structurally related ligands, which showed a good discrimination between CDK2 binders and nonbinders.

• 한국정보과학회논문지:데이타베이스
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• 제31권6호
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• pp.641-649
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• 2004

약물의 화학적 구조와 그 약물의 약리작용간의 연관성은, 'Medicinal Chemistry' 분야에서 활발히 연구된다. 이는 화학구조를 기반으로 하여 신약을 설계하려는 시도로서, 약학자는 신약 개발 시 만들고자 하는 약물과 비슷한 화학구조를 가지고 있는 기존 약물들에는 어떠한 것들이 있는지 조사하며, 특정 화학구조가 어떤 약물들에서 나타나는지 신속히 검색하기를 원한다. 이처럼 어떤 화차구조에서, 특정한 부분구조가 존재하는지를 검사하는 것을 부분구조검색(Substructure Searching)이라 하며, 이는 그래프 이론에서 NP-complete인 동형성 판정(Subgraph Isomorphism) 문제로 귀결된다. 검색 시간을 단축시키고자 여러 다른 전근방법들이 연구되었는데, 1990년대에는 구조에 대한 인덱스를 미리 만들어 RDBMS에 저장한 후, 검색시 이론 이용하여 성능을 높이는 방법으로 미국 특허를 획득한 RS3 시스템(http://www.acelrys.com/rs3)이 현재 상용화되어 쓰이고 있다. 본 논문에서는 RS3 시스템의 문제점을 규명하고, 이의 개선방안으로서 새로운 인덱스를 제안한다 RS3 시스템은 각 원자를 중심으로 다른 원자와의 구조를 문자연로 표현하고, 부분구조검색 쿼리를 부분문자열 검색을 실행함으로써 수행하는데, 이의 화학구조를 기술하는 인덱스에는 동일 원자, 동릴 결합에 대한 정렬이 불가능하여 재현율(Recall)과 정도(Precision)가 낮다. 이론 개선하기 위하여 본 논문에서는 2차원의 화학구조를 나누어 1차원의 구조 단편으로 만들고 이를 문자열로 기술하는 방안을 제시하며 구체적인 방법으로 한 인자를 중심으로 최소비용신장트리를 구성한 다음 레벨별로 경로를 나누어 기술하는 방안을 제안하며, 이와 같은 방법의 새로운 인덱스로 재현율과 정도가 급격히 향상됨을 보인다.

• Bulletin of the Korean Chemical Society
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• 제34권11호
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• pp.3429-3443
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• 2013

Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane helices. Recent pharmaceutical research has focused on the antagonism of CCR2 and candidate drugs are currently undergoing clinical studies for the treatment of diseases like arthritis, multiple sclerosis, and type 2 diabetes. In this study, we analyzed the time dependent behavior of CCR2 docked with a potent 4-azetidinyl-1-aryl-cyclohexane (4AAC) derivative using molecular dynamics simulations (MDS) for 20 nanoseconds (ns). Homology modeling of CCR2 was performed and the 4AAC derivative was docked into this binding site. The docked model of selected conformations was then utilized to study the dynamic behavior of the 4AAC enzyme complexes inside lipid membrane. MDS of CCR2-16b of 4AAC complexes allowed us to refine the system since binding of an inhibitor to a receptor is a dynamic process and identify stable structures and better binding modes. Structure activity relationships (SAR) for 4AAC derivatives were investigated and reasons for the activities were determined. Probable binding pose for some CCR2 antagonists were determined from the perspectives of binding site. Initial modeling showed that Tyr49, Trp98, Ser101, Glu291, and additional residues are crucial for 4AAC binding, but MDS analysis showed that Ser101 may not be vital. 4AAC moved away from Ser101 and the hydrogen bonding between 4AAC and Ser101 vanished. The results of this study provide useful information regarding the structure-based drug design of CCR2 antagonists and additionally suggest key residues for further study by mutagenesis.

• Bulletin of the Korean Chemical Society
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• 제26권11호
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• pp.1695-1700
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• 2005

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is an S-adenosylmethionine (SAM, AdoMet) dependent methyltransferase, and is related to the functions of the neurotransmitters in various mental processes, such as Parkinson’s disease. COMT inhibitors represent a new class of antiparkinson drugs, when they are coadministered with levodopa. Based on x-ray structure of rat COMT (rCOMT), the three dimensional structure of human COMT (hCOMT) was constructed by comparative homology modeling using MODELLER. The catalytic site of these two proteins showed subtle differences, but these differences are important to determine the characterization of COMT inhibitor. Ligand docking study is carried out for complex of hCOMT and COMT inhibitors using AutoDock. Among fifteen inhibitors chosen from world patent, nine models were energetically favorable. The average value of heavy atomic RMSD was 1.5 $\AA$. Analysis of ligand-protein binding model implies that Arg201 on hCOMT plays important roles in the interactions with COMT inhibitors. This study may give insight to develop new ways of antiparkinson drug.

• Bulletin of the Korean Chemical Society
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• 제35권9호
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• pp.2655-2659
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• 2014

Dual specificity protein phosphatase 4 (DUSP4) has been considered a promising target for the development of therapeutics for various human cancers. Here, we report the first example for a successful application of the structure-based virtual screening to identify the novel small-molecule DUSP4 inhibitors. As a consequence of the virtual screening with the modified scoring function to include an effective molecular solvation free energy term, five micromolar DUSP4 inhibitors are found with the associated $IC_{50}$ values ranging from 3.5 to $10.8{\mu}M$. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they may serve as a starting point of the structure-activity relationship study to optimize the medical efficacy. Structural features relevant to the stabilization of the new inhibitors in the active site of DUSP4 are discussed in detail.

• Journal of Ginseng Research
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• 제44권5호
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• pp.680-689
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• 2020

Background: Peptides have diverse and important physiological roles in plants and are ideal markers for species identification. It is unclear whether there are specific peptides in Panax quinquefolius L. (PQ). The aims of this study were to identify Quinetides, a series of diverse posttranslational modified native peptides of the ribonuclease-like storage protein (ginseng major protein), from PQ to explore novel peptide markers and develop a new method to distinguish PQ from Panax ginseng. Methods: We used different fragmentation modes in the LTQ Orbitrap analysis to identify the enriched Quinetide targets of PQ, and we discovered Quinetide markers of PQ and P. ginseng using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. These "peptide markers" were validated by simultaneously monitoring Rf and F11 as standard ginsenosides. Results: We discovered 100 Quinetides of PQ with various post-translational modifications (PTMs), including a series of glycopeptides, all of which originated from the protein ginseng major protein. We effectively distinguished PQ from P. ginseng using new "peptide markers." Four unique peptides (Quinetides TP6 and TP7 as markers of PQ and Quinetides TP8 and TP9 as markers of P. ginseng) and their associated glycosylation products were discovered in PQ and P. ginseng. Conclusion: We provide specific information on PQ peptides and propose the clinical application of peptide markers to distinguish PQ from P. ginseng.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7473-7482
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• 2013

The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.