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Identification of TLR2 modulators and exploration of possible binding modes
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | Sangdun Choi | - |
| dc.contributor.author | Durai, Prasannavenkatesh | - |
| dc.date.accessioned | 2018-11-08T08:11:42Z | - |
| dc.date.available | 2018-11-08T08:11:42Z | - |
| dc.date.issued | 2016-08 | - |
| dc.identifier.other | 22852 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/11504 | - |
| dc.description | 학위논문(박사)--아주대학교 일반대학원 :분자과학기술학과,2016. 8 | - |
| dc.description.tableofcontents | TOLL-LIKE RECEPTOR 2 1 Historical Background 1 Structure of TLR2 2 Ligand Recognition by TLR2 3 MyD88-dependent TLR2 Signaling 6 Role of TLR2 in Diseases 8 TOLL-LIKE RECEPTOR 2 ANTAGONISTS IDENTIFIED THROUGH VIRTUAL SCREENING AND EXPERIMENTAL VALIDATION 10 Introduction 10 Results 12 Discussion 27 RESULTS (EXTENDED ABSTRACTS OF MANUSCRIPTS) 29 Structure and dynamic behavior of Toll-like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum 29 MATERIALS AND METHODS 30 Computational Mutation Scanning and Pharmacophore Modeling 30 Pharmacophore-based Database Search and Isolation of Drug-like Molecules 31 Structure Preparation and Molecular Docking 32 MD Simulations, Binding Free Energy Calculations and Principal component analysis 33 Surface Plasmon Resonance Analysis 34 Cell Culture and Treatments 35 Western Blot 36 Interleukin-8 Secretion Assay 47 Cell Viability Assay 37 Statistical Analysis 38 FUTURE WORKS 38 REFERENCES 39 APPENDIX 45 Structure and dynamic behavior of Toll-like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum 45 SUPPORTING INFORMATION 63 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Identification of TLR2 modulators and exploration of possible binding modes | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.department | 일반대학원 분자과학기술학과 | - |
| dc.date.awarded | 2016. 8 | - |
| dc.description.degree | Doctoral | - |
| dc.identifier.localId | 758525 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000022852 | - |
| dc.subject.keyword | Bioinformatics | - |
| dc.description.alternativeAbstract | Toll-like receptor 2 (TLR2) antagonists are key therapeutic targets because they inhibit several inflammatory diseases caused by surplus TLR2 activation. We identified two novel TLR2 antagonists, C11 and C13, through pharmacophore-based virtual screening. At 10 µM, C13 inhibited almost 67%, and C11 inhibited more than 44%, of Interleukin-8 production in human embryonic kidney TLR2 overexpressing cells. Moreover, these two compounds bind directly to the human recombinant TLR2 ectodomain during surface plasmon resonance analysis, and did not affect the cell viability in MTT assay. In total, two virtually screened molecules, C11 and C13, were experimentally proven to be effective, and thus, will provide new understanding into the structure of TLR2 antagonists and help for the development of TLR2 drug molecules. Plasmodium falciparum, a protozoan pathogen causes malaria via glycosylphosphatidylinositols (GPIs). GPIs activate TLR2 signaling to protect humans via the induction of proinflammatory cytokines. Biological studies provided us the evidence of TLR2-GPIs interactions. However, the binding modes of the molecules that is key to therapeutics were unknown. To unravel this, we used computational approaches such as computational docking, MD simulations and essential dynamics. We identified the GPIs-induced conformational changes in the ligand binding region and C-term of TLR2 subfamily members, and based on the results we proposed that GPIs binding are similar to already known synthetic ligands and the acyl chains in GPIs may mainly involve in dimerization of TLR2. | - |
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