微管在细胞有丝分裂过程中发挥着重要的作用,已成为目前全新靶向抗癌药物研究与开发的重要靶点之一。微管抑制剂主要通过干扰微管的解聚或稳定作用而发挥抗癌功效,已在肿瘤临床治疗方面占据了重要地位。但目前所报道的抑制剂数量较少,且大部分主要源自天然产物或其衍生物,骨架结构类型非常有限。
图:筛选到的新型抑制剂在细胞中的测试
张会老师课题组采用计算虚拟筛选技术开展了靶向紫杉醇位点微管新型稳定剂的筛选研究,发现了多个活性较好的新型骨架的微管抑制剂。如采用分子对接技术从BioDiversity数据库中筛选出50个候选化合物,体外生物活性实验表明,2个新型稳定剂能够有效促进体外微管聚合,抑制肿瘤细胞增殖,阻滞细胞周期在G2/M期,诱导细胞凋亡。其次,采用分子动力学和MM/PBSA进一步探讨化合物与微管蛋白结合位点的活性作用机理,为先导化合物的结构优化修饰提供重要的理论指导。该研究成果已发表在《Bioorganic Chemistry》(IF2021=5.275,中科院2区)。
该课题组近期在微管抑制剂方面取得了多项成果,连续发表于《Journal of Cellular Biochemistry》(IF2021=4.429,中科院3区)、《Chemico-Biological Interactions》(IF2021=5.192,中科院2区)和《Life Sciences》(IF2021=5.037,中科院2区)。这些筛选到的微管新型抗肿瘤先导化合物对靶向微管抗肿瘤治疗具有重要意义。
论文链接:
1. Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation, Journal of Cellular Biochemistry, 2021, https://doi.org/10.1002/jcb.30077
2. Discovery of microtubule stabilizers with novel scaffold structures based on virtual screening, biological evaluation, and molecular dynamics simulation, Chemico-Biological Interactions, 2022, https://doi.org/10.1016/j.cbi.2021.109784
3. Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing, Bioorganic Chemistry, 2022, https://doi.org/10.1016/j.bioorg.2022.105722
4. Wangzaozin A, a Potent Novel Microtubule Stabilizer, Targets Both the Taxane and Laulimalide Sites on β-tubulin, Life Sciences, 2022, https://doi.org/10.1016/j.lfs.2022.120583