State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China.
State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China.
Ecotoxicol Environ Saf. 2024 Apr 1;274:116187. doi: 10.1016/j.ecoenv.2024.116187. Epub 2024 Mar 8.
Due to the adverse environmental impacts of toxic heavy metal-based antifoulants, the screening of environmentally friendly antifoulants has become important for the development of marine antifouling technology. Compared with the traditional lengthy and costly screening method, computer-aided drug design (CADD) offers a promising and efficient solution that can accelerate the screening process of green antifoulants. In this study, we selected barnacle chitin synthase (CHS, an important enzyme for barnacle settlement and development) as the target protein for docking screening. Three CHS genes were identified in the barnacle Amphibalanus amphitrite, and their encoded proteins were found to share a conserved glycosyltransferase domain. Molecular docking of 31,561 marine natural products with AaCHSs revealed that zoanthamine alkaloids had the best binding affinity (-11.8 to -12.6 kcal/mol) to AaCHSs. Considering that the low abundance of zoanthamine alkaloids in marine organisms would limit their application as antifoulants, a marine fungal-derived natural product, mycoepoxydiene (MED), which has a similar chemical structure to zoanthamine alkaloids and the potential for large-scale production by fermentation, was selected and validated for stable binding to AaCHS2L2 using molecular docking and molecular dynamics simulations. Finally, the efficacy of MED in inhibiting cyprid settlement of A. amphitrite was confirmed by a bioassay that demonstrated an EC of 1.97 μg/mL, suggesting its potential as an antifoulant candidate. Our research confirmed the reliability of using AaCHSs as antifouling targets and has provided insights for the efficient discovery of green antifoulants by CADD.
由于有毒重金属基防污剂对环境的不利影响，筛选环保型防污剂对于海洋防污技术的发展变得尤为重要。与传统的漫长且昂贵的筛选方法相比，计算机辅助药物设计（CADD）提供了一种有前途且高效的解决方案，可以加速绿色防污剂的筛选过程。在本研究中，我们选择藤壶几丁质合酶（CHS，藤壶附着和发育的重要酶）作为对接筛选的靶标蛋白。在藤壶 Amphibalanus amphitrite 中鉴定了三个 CHS 基因，它们编码的蛋白质被发现共享一个保守的糖基转移酶结构域。对 31561 种海洋天然产物与 AaCHSs 的分子对接表明，zoanthamine 生物碱对 AaCHSs 的结合亲和力最佳（-11.8 至-12.6 kcal/mol）。考虑到海洋生物中 zoanthamine 生物碱的低丰度会限制其作为防污剂的应用，我们选择了一种海洋真菌来源的天然产物 mycoepoxydiene（MED），它具有与 zoanthamine 生物碱相似的化学结构，并且可以通过发酵进行大规模生产，并用分子对接和分子动力学模拟验证了其与 AaCHS2L2 的稳定结合。最后，通过生物测定证实 MED 抑制藤壶 Amphitrite 的幼体附着的功效，其 EC 值为 1.97 μg/mL，表明其作为防污剂候选物的潜力。我们的研究证实了使用 AaCHSs 作为防污靶标的可靠性，并为 CADD 高效发现绿色防污剂提供了思路。
