化疗是最完善和有效的癌症治疗方法之一。然而,非肿瘤相关损伤限制了治疗的有效性和安全性。近几十年来,我们对癌症表观遗传学的日益理解导致了新的治疗选择和更好的患者预后的潜力。在癌症中,表观遗传变化很普遍,特别是组蛋白脱乙酰酶(HDAC)的表达和活性增加。药物是修饰DNA和染色质结构的化学试剂,其促进转录和转录后变化的破坏。第一代表观药物包括HDAC抑制剂(HDACi)(批准用于治疗血液恶性肿瘤)具有各种不良反应,要求发现和开发可能有益于癌症治疗的潜在天然HDACi,尤其是血液恶性肿瘤。姜黄素(二铁酰基甲烷),一种多酚,姜黄的成分,是一种众所周知的消炎药,抗氧化,和抗血脂药,最近被证明是一种泛HDACi。然而,姜黄中其他类姜黄素作为panHDACi的潜力仍未被开发。(i)针对人类组蛋白去乙酰化酶(HDAC)I类,虚拟筛选姜黄素和类姜黄素(去甲氧基姜黄素[DMC]和双去甲氧基姜黄素[BDMC]),II和IV酶与FDA批准的人类HDAC相比,它们的panHDAC抑制活性可在市场上购买,并且还可以(ii)预测姜黄素的药物相似性和ADME/毒性,类姜黄素和通过计算方法批准的HDACis。对人类HDACI类进行了同源建模,然后进行对接,II和IV酶与姜黄素,去甲氧基姜黄素,双去甲氧基姜黄素和5个参考HDACi化合物伏立诺他(SAHA),曲古他汀A(TSA),Chidamide,Romidepsin,和Panobinostat来了解蛋白质-配体相互作用和结合效率。Further,预测了具有低结合能的研究配体的药代动力学特性和Lipinski\的5法则。我们的研究表明,与标准HDACi(姜黄素,DMC,BDMC,Belinostat,Chidamide,Romidepsin,Panobinostat,曲古他汀A和伏立诺他)。同样,所有选择的配体分子,除了Romidepsin(折射率>130m3mol-1),遵守Lipinski的规则,没有天然化合物(姜黄素,DMC,BDMC)也报告了任何毒性和诱变性质,与化学药物相比,所有天然化合物的致死剂量(LD50)更高。由于人Zn+HDAC之间的高结合亲和力,BDMC可能是比姜黄素和DMC潜在的panHDACi。我们本研究的结果可用于设计和开发针对几种类型的癌症具有更好的HDAC抑制活性的新型化合物。此外,这些发现可以通过体外研究和临床试验得到验证,以评估天然HDACi联合标准化疗方案治疗癌症患者的生存结局.
■在线版本包含补充材料,可在10.1007/s40203-024-00221-4获得。
Chemotherapy is one of the most well-established and effective cancer treatments available. However, non-tumor-associated damage restrict the treatment\'s effectiveness and safety. Our growing understanding of cancer epigenetics has resulted in new therapeutic options and the potential of better patient outcomes in recent decades. In cancer, epigenetic changes are widespread, particularly increased expression and activity of histone deacetylases (HDACs). Epi-drugs are chemical agents that modify the structure of DNA and chromatin facilitating disruption of transcriptional and post-transcriptional changes. First generation epi-drugs include HDAC inhibitors (
HDACi) (approved to treat hematological malignancies) harbor various adverse effects demanding the discovery and development of potential natural
HDACi that might benefit cancer treatment especially in hematological malignancies. Curcumin (diferuloylmethane), a polyphenolic, component of Curcuma longa, is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to be a pan
HDACi. Yet the potential of other curcuminoids in Curcuma longa as pan
HDACi remains unexplored. (i) To virtually screen curcumin and curcuminoids (Desmethoxycurcumin [DMC] & Bisdemethoxycurcumin [BDMC]) against human Histone deacetylase (HDAC) class I, II and IV enzymes in comparison to their pan HDAC inhibition activity with FDA approved human HDACis available in market and also (ii) to predict the drug likeness property and ADME/ toxicity of curcumin, curcuminoids and approved HDACis via computational approach. Homology modelling followed by docking was performed for human HDAC class I, II and IV enzymes with curcumin, Desmethoxycurcumin, Bisdemethoxycurcumin and with 5 reference HDACi compounds Vorinostat (SAHA), Trichostatin A (TSA), Chidamide, Romidepsin, and Panobinostat to understand the protein -ligand interactions and binding efficiencies. Further, the study ligands with low binding energy were predicted for pharmacokinetic properties and Lipinski\'s rule of 5. Our study revealed that BDMC followed by DMC and curcumin had high inhibitory effect by interacting at the active site of Zn+ HDACs similar to that of the standard HDACi (curcumin, DMC, BDMC, Belinostat, Chidamide, Romidepsin, Panobinostat, Trichostatin A and Vorinostat). Likewise, all of the chosen ligand molecules, with the exception of Romidepsin (refractive index > 130 m3mol-1), adhered to Lipinski\'s rule of five and none of the natural compounds (curcumin, DMC, BDMC) did report any toxicity and mutagenic property also, the lethal doses (LD50) of all the natural compounds were higher when compared to chemical drugs. BDMC could be a potential pan
HDACi than curcumin and DMC owing to high binding affinity among human Zn+ HDACs. The results of our present study can be useful for the design and development of novel compounds having better HDAC inhibitory activity against several types of cancers. Moreover, these findings could be validated with invitro investigations and by clinical trials to evaluate the survival outcomes in cancer patients when treated with the natural HDACi along with standard chemo regimen.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40203-024-00221-4.