Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Humans MeSH
- Molecular Chaperones genetics metabolism therapeutic use MeSH
- Opsins * genetics MeSH
- Reproducibility of Results MeSH
- Retinitis Pigmentosa * drug therapy genetics metabolism MeSH
- Rod Opsins chemistry genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Molecular Chaperones MeSH
- Opsins * MeSH
- Rod Opsins MeSH
N-terminal P23H opsin mutation accounts for most of retinitis pigmentosa (RP) cases. P23H functions and folding can be rescued by small chaperone ligands, which contributes to validate mutant opsin as a suitable target for pharmacological treatment of RP. However, the lack of structural details on P23H mutant opsin strongly impairs drug design, and new chemotypes of effective chaperones of P23H opsin are in high demand. Here, a computational-boosted workflow combining homology modeling with molecular dynamics (MD) simulations and virtual screening was used to select putative P23H opsin chaperones among different libraries through a structure-based approach. In vitro studies corroborated the reliability of the structural model generated in this work and identified a number of novel chemotypes of safe and effective chaperones able to promote P23H opsin trafficking to the outer cell membrane.
Department of Chemistry Faculty of Science and Engineering Swansea University Swansea SA2 8PP UK
School of Biosciences Cardiff University Cardiff CF10 3AX UK
School of Pharmacy and Pharmaceutical Sciences Cardiff University Cardiff CF10 3NB UK
Vysoká Škola Chemicko Technologiká Praha Prague 166 28 Czech Republic
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