Medoro Alessandro, Scapagnini Giovanni, Brogi Simone, Jafar Tassadaq Hussain, Trung Truong Tan, Saso Luciano, Davinelli Sergio
Department of Medicine and Health Sciences "V. Tiberio", University of Molise, 86100 Campobasso, Italy.
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Pharmaceuticals (Basel). 2024 Nov 27;17(12):1597. doi: 10.3390/ph17121597.
: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. /: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions. Astaxanthin, siphonaxanthin, and prasinoxanthin were identified as the top candidates, demonstrating strong binding affinity (-10.5, -10.3, and -9.4 Kcal/mol, respectively) and stable interactions with several known key residues within the active site of PCSK9, including Pro-331, Arg-357, Cys-358, Val-359, Asp-360, Ile-416, Leu-436, Thr-437, Pro-438, Leu-440, Arg-458, Val-460, Trp-461, Arg-476, Cys-477, Ala-478, Ala-649, Val-650, and Asp-651. Density functional theory analysis confirmed the stability of astaxanthin and its favorable electronic properties, suggesting its potential as an effective inhibitor. Molecular dynamics simulations of the PCSK9-astaxanthin complex revealed sustained structural stability and key interactions critical for maintaining the functional integrity of the protein. : These findings provide evidence that specific carotenoids, particularly astaxanthin, may offer a cost-effective alternative to existing PCSK9 inhibitors, providing a potential approach for managing cholesterol levels and reducing cardiovascular risk. Pre-clinical and clinical validations are required to confirm the therapeutic potential of these compounds.
本研究调查了绿藻来源的类胡萝卜素作为前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）天然抑制剂的潜力，PCSK9是胆固醇代谢的关键调节因子。PCSK9促进低密度脂蛋白受体（LDLR）的降解，从而提高血液胆固醇水平并增加心血管疾病风险。我们筛选了27种类胡萝卜素与PCSK9的药效团拟合得分，并鉴定出14种进行结合亲和力和分子相互作用分析。虾青素、管鞭藻黄素和原始叶黄素被确定为最佳候选物，显示出强结合亲和力（分别为-10.5、-10.3和-9.4千卡/摩尔），并与PCSK9活性位点内的几个已知关键残基有稳定相互作用，包括Pro-331、Arg-357、Cys-358、Val-359、Asp-360、Ile-416、Leu-436、Thr-437、Pro-438、Leu-440、Arg-458、Val-460、Trp-461、Arg-476、Cys-477、Ala-478、Ala-649、Val-650和Asp-651。密度泛函理论分析证实了虾青素的稳定性及其有利的电子性质，表明其作为有效抑制剂的潜力。PCSK9-虾青素复合物的分子动力学模拟揭示了持续的结构稳定性和对维持蛋白质功能完整性至关重要的关键相互作用。这些发现提供了证据，表明特定的类胡萝卜素，特别是虾青素，可能为现有的PCSK9抑制剂提供一种经济有效的替代方案，为管理胆固醇水平和降低心血管风险提供了一种潜在方法。需要进行临床前和临床验证以确认这些化合物的治疗潜力。
