Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach,Journal of Chemical Information and Modeling

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Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-11-11 , DOI: 10.1021/acs.jcim.2c01040
Francesca Picarazzi ₁ , Marika Zuanon ₂ , Gaia Pasqualetto ₃ , Silvia Cammarone ₄ , Isabella Romeo ₄ , Mark T Young ₂ , Andrea Brancale _{3,

5} , Marcella Bassetto ₆ , Mattia Mori ₁

Affiliation

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.

中文翻译：

通过基于计算机结构的方法鉴定结合 P23H 突变视蛋白的小分子伴侣

N 末端 P23H 视蛋白突变占大多数视网膜色素变性 (RP) 病例。P23H 功能和折叠可以通过小伴侣配体挽救，这有助于验证突变视蛋白作为 RP 药物治疗的合适靶点。然而，缺乏 P23H 突变体视蛋白的结构细节严重损害了药物设计，因此迫切需要 P23H 视蛋白有效分子伴侣的新化学型。在这里，将同源建模与分子动力学 (MD) 模拟和虚拟筛选相结合的计算增强工作流程用于通过基于结构的方法在不同库中选择推定的 P23H 视蛋白伴侣。

更新日期：2022-11-11

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