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.
Picarazzi, F., Zuanon, M., Pasqualetto, G., Cammarone, S., Romeo, I., Young, M.T., et al. (2022). Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 62(22), 5794-5805 [10.1021/acs.jcim.2c01040].
Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach
Picarazzi, Francesca;Mori, Mattia
2022-01-01
Abstract
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.File | Dimensione | Formato | |
---|---|---|---|
125-JChemInfModel_2022.pdf
non disponibili
Descrizione: Articolo
Tipologia:
PDF editoriale
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
8.57 MB
Formato
Adobe PDF
|
8.57 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
https://hdl.handle.net/11365/1221078