Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach

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.