Identification of small molecular chaperones binding p23h mutant opsin through an in silico structure-based approach

Picarazzi, Francesca, Zuanon, Marika, Pasqualetto, Gaia, Cammarone, Silvia, Romeo, Isabella, Young, Mark T. ORCID: https://orcid.org/0000-0002-9615-9002, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Bassetto, Marcella ORCID: https://orcid.org/0000-0002-2491-5868 and Mori, Mattia 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) , pp. 5794-5805. 10.1021/acs.jcim.2c01040

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	1549-9596
Date of First Compliant Deposit:	15 November 2022
Date of Acceptance:	1 November 2022
Last Modified:	06 Jan 2024 05:10
URI:	https://orca.cardiff.ac.uk/id/eprint/154186

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