Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, PR China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Bioorg Chem. 2018 Dec;81:672-680. doi: 10.1016/j.bioorg.2018.09.029. Epub 2018 Sep 20.
It is still challenging to determine the potential targets of natural products, which is essential for further drug research and development. Due to its novel mechanism of action of inducing autophagy effects in breast cancer cells, asperphenamate has received our considerable attention. However, its unknown target inevitably impedes further study. In our previous work, the target enzyme of asperphenamate was predicted as cathepsin by the natural product consensus pharmacophore strategy. Then, asperphenamate and its three derivatives were chosen to study in detail by molecular docking calculations with AutoDock 4 suite. The docking results showed the three derivatives interacted more tightly with either cathepsin L or cathepsin S than with asperphenamate. The ortho-benzyloxyl phenylacetyl derivative 1 andp-toluenesulfonyl derivative 3 showed similar interactions with cathepsin L and adopted a better geometric shape within the binding pocket than did the N-CBZ-piperidyl analog 2. On the other hand, compound 2 formed more hydrogen bonds than 1 and 3 to make it tightly bind within cathepsin S. The cathepsin inhibitory activity assay verified the molecular simulation results. Compound 2 was remarkably less active than 1 and 3 against cathepsin L. However, compound 2 showed the strongest potency against cathepsin S with IC of 13.12 ± 0.29 μM. Considering that cathepsin S plays a vital role in the process of metastasis in breast cancer cells, the inhibitory effect of 2 on migration and invasion was further studied in human breast cancer MDA-MB-231 cells by wound healing and transwell chamber assays. The results illustrated that 2 exhibited an apparent inhibitory ability to the metastasis of MDA-MB-231 cells. Next, 2 will be chosen as a lead compound to develop novel double functional chemotherapeutic agents with both novel mechanisms of action against apoptosis-resistant cancer cells, such as inducing autophagy and inhibiting cancer metastasis.
确定天然产物的潜在靶点仍然具有挑战性，这对于进一步的药物研究和开发至关重要。由于其在乳腺癌细胞中诱导自噬作用的新颖作用机制，asperphenamate 引起了我们的极大关注。然而，其未知的靶点不可避免地阻碍了进一步的研究。在我们之前的工作中，asperphenamate 的靶酶通过天然产物共识药效团策略预测为组织蛋白酶。然后，选择 asperphenamate 及其三个衍生物通过 AutoDock 4 套件的分子对接计算进行详细研究。对接结果表明，三个衍生物与组织蛋白酶 L 或组织蛋白酶 S 的相互作用比与 asperphenamate 更紧密。邻苄氧基苯乙酰基衍生物 1 和对甲苯磺酰基衍生物 3 与组织蛋白酶 L 表现出相似的相互作用，并在结合口袋内采用了更好的几何形状，而 N-CBZ-哌啶类似物 2 则不然。另一方面，化合物 2 与 1 和 3 形成更多氢键，使其在组织蛋白酶 S 内紧密结合。组织蛋白酶抑制活性测定验证了分子模拟结果。化合物 2 对组织蛋白酶 L 的活性明显低于 1 和 3。然而，化合物 2 对组织蛋白酶 S 的抑制作用最强，IC 为 13.12±0.29μM。考虑到组织蛋白酶 S 在乳腺癌细胞转移过程中起着至关重要的作用，进一步研究了化合物 2 对人乳腺癌 MDA-MB-231 细胞迁移和侵袭的抑制作用通过划痕愈合和 Transwell 室测定。结果表明，2 对 MDA-MB-231 细胞的转移表现出明显的抑制能力。接下来，2 将被选为一种先导化合物，以开发针对凋亡抗性癌细胞（如诱导自噬和抑制癌症转移）的新型双重功能化疗药物。
