对Racl蛋白抑制作用的生物还原剂的虚拟筛选

Virtual screening for bioreductive inhibitors of Racl protein

;乏氧是肿瘤组织的重要特点,而在肿瘤组织中高表达的Racl蛋白是与氧化还原过程密切相关的蛋白质,且参与肿瘤发展的多个过程。Racl抑制剂可有效抑制肿瘤细胞的侵润与发展。因此,有效的Racl抑制剂可成为潜在抗癌药物。目前能用于临床治疗肿瘤的Racl抑制剂鲜有报道。生物还原剂是一大类对乏氧细胞有特异毒性的化合物,可以靶向作用于乏氧细胞,抑制乏氧肿瘤细胞的生长。本文根据Racl的三维结构,利用虚拟筛选软件PyRx,在化合物库中对约1.5万个硝基杂环化合物、芳香氮氧化合物、脂肪氮氧化合物、醌类化合物等生物还原剂进行筛选,根据结合能、结合位点、结合模式等条件筛选出6个候选Racl抑制剂,为靶向乏氧肿瘤细胞的生物还原剂的开发、构效关系研究提供理论依据。

Solid tumors are often hypoxia. Racl （ras-related C3 botulinum toxin substrate 1） plays vital role in tumor progression and over-expression of Racl was observed in many types of tumor. Therefore, Racl inhibitors are potential anti-cancer drugs. Bioreductive drugs targeted tumor hypoxia and inhibited the growth of hypoxia tumor cells. However, there were few reports about Rac I inhibitors in clinic tumor treatment. Here we describe the virtual screening for bioreductive drugs that target Racl from 15000 bioreductive compounds such as quinonoids, nitro compounds, aromatic N-oxides and aliphatic N-oxides, using the 3D structure of Racl. Six potential Racl bioreductive inhibitors were screened after analyzing the binding energy, and binding mode of the docking compounds. Our results provide new scaffold for bioreductive drug development and structure-activity relationship which targeted hypoxic tumor cells.