海洋来源的 SLC7A11 抑制剂的鉴定：分子对接、基于结构的虚拟筛选、细胞毒性预测和分子动力学模拟。
Identification of Marine-Derived SLC7A11 Inhibitors: Molecular Docking, Structure-Based Virtual Screening, Cytotoxicity Prediction, and Molecular Dynamics Simulation.
发表日期：2024 Aug 20
作者：
Jiaqi Chen, Xuan Li, Jiahua Tao, Lianxiang Luo
来源：
Marine Drugs
摘要：
寻找针对铁死亡的抗癌药物是一个有前途的研究途径。 SLC7A11 是参与铁死亡的关键蛋白，已被确定为药物开发的潜在靶点。通过筛选工作，设计了新型 SLC7A11 抑制剂，旨在促进铁死亡并最终消除癌细胞。我们最初使用药效团和 2D-QSAR 模型筛选了 563 个小分子。以 Erastin 作为阳性对照进行分子对接和 ADMET 毒性预测，确定小分子 42711 和 27363 为对 SLC7A11 具有强抑制活性的先导化合物。进一步优化导致了新抑制剂结构的开发（42711_11）。分子对接和 ADMET 重新筛选证明了该小分子的片段替换成功。最终的分子动力学模拟也证实了其与蛋白质的稳定相互作用。这些发现代表了朝着开发铁死亡相关疾病的新治疗策略迈出的重要一步。
The search for anticancer drugs that target ferroptosis is a promising avenue of research. SLC7A11, a key protein involved in ferroptosis, has been identified as a potential target for drug development. Through screening efforts, novel inhibitors of SLC7A11 have been designed with the aim of promoting ferroptosis and ultimately eliminating cancer cells. We initially screened 563 small molecules using pharmacophore and 2D-QSAR models. Molecular docking and ADMET toxicity predictions, with Erastin as a positive control, identified the small molecules 42711 and 27363 as lead compounds with strong inhibitory activity against SLC7A11. Further optimization resulted in the development of a new inhibitor structure (42711_11). Molecular docking and ADMET re-screening demonstrated successful fragment substitution for this small molecule. Final molecular dynamics simulations also confirmed its stable interaction with the protein. These findings represent a significant step towards the development of new therapeutic strategies for ferroptosis-related diseases.