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Identification of TLR2 modulators and exploration of possible binding modes
- Author(s)
- Durai, Prasannavenkatesh
- Advisor
- Sangdun Choi
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2016-08
- Language
- eng
- Keyword
- Bioinformatics
- Alternative Abstract
- 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.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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