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.

中文翻译：

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表观遗传调节剂作为针对刺猬通路治疗癌症的潜在多靶点药物。

众所周知，音速刺猬信号在调节胚胎发育，癌症干细胞维持和组织模式中起着至关重要的作用。据报道，刺猬信号失调会影响各种人类恶性肿瘤的发生和药物反应。考虑到它们在预防癌症祖细胞的发展，杀死耐药细胞以及指示肿瘤抑制基因和癌基因的“开/关”转换方面的有效性，依赖于DNA甲基转移酶和组蛋白脱乙酰基酶抑制剂的表观遗传疗法被提议为潜在的候选药物。在这种对接方法中，使用多药理学方法对表观遗传调节剂在抑制SHH途径的关键调节因子（即声波刺猬，平滑肌和Gli）中的效率进行了虚拟筛选。使用AutoDock静脉将对照药物和表观遗传调节剂与PDB蛋白结构对接，并进一步检查其药物相似性。使用VMD和NAMD进行了进一步的分子动力学模拟，并使用MMP / GBSA能量计算来验证配体-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信号方面表现出多目标方法。这是第一个将这些表观遗传药物报告为潜在的多靶点刺猬途径抑制剂的研究。从而，