Di Stefano Miriana, Ghilardi Maria, Poles Clarissa, Piazza Lisa, Demontis Gian Carlo, Poli Giulio, Tuccinardi Tiziano, Macchia Marco
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Telethon Institute of Genetics and Medicine, 80078 Naples, Italy.
Molecules. 2025 May 26;30(11):2328. doi: 10.3390/molecules30112328.
Rhodopsin, a G-protein-coupled receptor (GPCR) comprising the protein opsin covalently linked to the chromophore 11-cis retinal, is pivotal in visual phototransduction. Mutations in the gene encoding rhodopsin (RHO) can cause opsin misfolding or reduce its stability, resulting in retinal degenerative disorders such as retinitis pigmentosa (RP). Current therapeutic strategies employing retinoid-based chaperones partially rescue the folding and trafficking of mutant rhodopsin, but are limited by inherent toxicity and instability due to photoinduced isomerization. In the present work, a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations was employed, leading to the identification of a novel non-retinoid opsin ligand that can potentially act as a pharmacological chaperone. Biological validation confirmed that the compound binds opsin effectively, representing a valuable starting point for structure-based optimization studies aimed at identifying new opsin stabilizers.
视紫红质是一种G蛋白偶联受体（GPCR），由与发色团11-顺式视黄醛共价连接的视蛋白组成，在视觉光转导中起关键作用。编码视紫红质（RHO）的基因突变可导致视蛋白错误折叠或降低其稳定性，从而引发视网膜退行性疾病，如色素性视网膜炎（RP）。目前采用基于类视黄醇伴侣的治疗策略可部分挽救突变型视紫红质的折叠和转运，但由于光诱导异构化导致的固有毒性和不稳定性而受到限制。在本研究中，采用了基于药效团的虚拟筛选方案，并结合分子对接和分子动力学模拟，从而鉴定出一种新型非类视黄醇视蛋白配体，其有可能作为一种药理伴侣发挥作用。生物学验证证实该化合物能有效结合视蛋白，这是旨在鉴定新的视蛋白稳定剂的基于结构优化研究的一个有价值的起点。
