Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro
Language English Country France Media print-electronic
Document type Journal Article
PubMed
29407964
DOI
10.1016/j.ejmech.2017.12.074
PII: S0223-5234(17)31105-4
Knihovny.cz E-resources
- Keywords
- Adjuvants, Innate immunity system, PRR, TLR4, Virtual screening,
- MeSH
- Cell Line MeSH
- Small Molecule Libraries chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Ligands MeSH
- Molecular Structure MeSH
- Computer Simulation * MeSH
- Drug Evaluation, Preclinical MeSH
- Drug Design * MeSH
- Molecular Docking Simulation MeSH
- Toll-Like Receptor 4 antagonists & inhibitors MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Small Molecule Libraries MeSH
- Ligands MeSH
- TLR4 protein, human MeSH Browser
- Toll-Like Receptor 4 MeSH
The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.
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