Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Gram-Lavale, Taluka-Mulshi, Pune, 412115, India.
Protein J. 2019 Oct;38(5):537-550. doi: 10.1007/s10930-019-09832-9.
The Sonic hedgehog signalling is known to play a crucial role in regulating embryonic development, cancer stem cell maintenance and tissue patterning. Dysregulated hedgehog signalling has been reported to affect tumorigenesis and drug response in various human malignancies. Epigenetic therapy relying on DNA methyltransferase and Histone deacetylase inhibitors are being proposed as potential drug candidates considering their efficiency in preventing development of cancer progenitor cells, killing drug resistant cells and also dictating "on/off" switch of tumor suppressor genes and oncogenes. In this docking approach, epigenetic modulators were virtually screened for their efficiency in inhibiting key regulators of SHH pathway viz., sonic hedgehog, Smoothened and Gli using polypharmacological approach. The control drugs and epigenetic modulators were docked with PDB protein structures using AutoDock vina and further checked for their drug-likeness properties. Further molecular dynamics simulation using VMD and NAMD, and MMP/GBSA energy calculation were employed for verifying the stability and entropy of the ligand-receptor complex. EPZ-6438 and GSK 343 (EZH2 inhibitors), CHR 3996 and Mocetinostat (HDAC inhibitors), GSK 126 (HKMT inhibitor) and UNC 1215 (L3MBTL3 antagonist) exhibited multiple-targeted approach in modulating HH signalling. This is the first study to report these epigenetic drugs as potential multi-targeted hedgehog pathway inhibitors. Thus, epigenetic polypharmacology approach can be explored as a better alternative to challenges of acute long term toxicity and drug resistance occurring due to traditional single targeted chemotherapy in the future.
已知 Sonic hedgehog 信号通路在调节胚胎发育、癌症干细胞维持和组织模式形成方面发挥着关键作用。失调的 hedgehog 信号通路已被报道会影响各种人类恶性肿瘤的肿瘤发生和药物反应。依赖于 DNA 甲基转移酶和组蛋白去乙酰化酶抑制剂的表观遗传疗法被认为是潜在的药物候选物，因为它们在防止癌症祖细胞发育、杀死耐药细胞以及决定肿瘤抑制基因和癌基因的“开/关”开关方面具有效率。在这种对接方法中，通过多药理学方法虚拟筛选了表观遗传调节剂，以抑制 SHH 通路的关键调节剂，即 sonic hedgehog、Smoothened 和 Gli。使用 AutoDock vina 将对照药物和表观遗传调节剂与 PDB 蛋白结构对接，并进一步检查其类药性。进一步使用 VMD 和 NAMD 进行分子动力学模拟，以及 MMP/GBSA 能量计算，以验证配体-受体复合物的稳定性和熵。EPZ-6438 和 GSK 343（EZH2 抑制剂）、CHR 3996 和 Mocetinostat（HDAC 抑制剂）、GSK 126（HKMT 抑制剂）和 UNC 1215（L3MBTL3 拮抗剂）在调节 HH 信号方面表现出多靶向方法。这是首次报道这些表观遗传药物作为潜在的多靶向 hedgehog 通路抑制剂的研究。因此，表观遗传多药理学方法可以作为未来克服传统单一靶向化疗引起的急性长期毒性和耐药性挑战的更好替代方法。
