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Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro
J. Honegr, D. Malinak, R. Dolezal, O. Soukup, M. Benkova, L. Hroch, O. Benek, J. Janockova, K. Kuca, R. Prymula,
European journal of medicinal chemistry.
2018 ;
146 (-) :
38-46.
[pub] 20180111
Language English Country France
Document type Journal Article
Persistent link
https://www.medvik.cz/link/bmc18010187
- 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
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.
References provided by Crossref.org
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