Novel Thiosemicarbazide Hybrids with Amino Acids and Peptides Against Hepatocellular Carcinoma: A Molecular Designing Approach Towards Multikinase Inhibitor
Novel Thiosemicarbazide Hybrids with Amino Acids and Peptides Against Hepatocellular Carcinoma: A Molecular Designing Approach Towards Multikinase Inhibitor
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DOI：
10.2174/1573409911666151103114300
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发表时间：
2015-01-01
影响因子：
1.7
通讯作者：
Samanta, Subir
中科院分区：
文献类型：
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作者：
Chacko, Shinu;Samanta, Subir
肝细胞癌是最常见的原发性肝脏恶性肿瘤。多药耐药性的产生是抗癌药物获得成功的主要障碍。由于生物活性化合物与氨基酸或肽的杂交体可能具有靶向特异性和较低的毒性，因此本研究进行了抗肝细胞癌的氨基硫脲与氨基酸或肽的杂交体的设计和对接研究。所有结构都在2D平台中绘制，并使用ChemDraw 10.0转换到3D平台。通过使用QikProp 3.0进行ADME性质的评价以检查口服递送的可能性。使用Pro-Tox网络服务器进行LD 50值的计算机模拟预测。有趣的是，发现与氨基酸的缀合降低了毒性并增加了氨基硫脲的治疗指数。最后，利用Glide 5.0，Schrodinger 8.5将所有化合物对接到血管内皮生长因子受体-2和检查点激酶-1的晶体结构，以了解配体与受体的相互作用。已经发现大量的衍生物在两种受体中都有活性，并且还显示出与索拉非尼相似的多激酶抑制活性，对肝细胞癌具有抑制作用。此外，需要进行湿实验室合成、体外ADMET和生物筛选研究，以证明所设计的化合物如分子建模所预测的那样对肝细胞癌有效。然而，如分子建模所预测的，所设计的化合物对肝细胞癌的功效需要通过湿实验室合成、体外ADMET和生物筛选研究来证实。
Hepatocellular Carcinoma is the most common primary malignant tumor of the liver. Development of multidrug resistance is the main obstacle to the success of anticancer drugs. In this study, designing and docking study of thiosemicarbazide hybrids with amino acids or peptides against hepatocellular carcinoma was performed since hybrids of biologically active compounds with amino acids or peptides may show target specificity and lower toxicity. All the structures were drawn in 2D platform and converted to the 3D platform using ChemDraw 10.0. Evaluations of ADME properties were done by using QikProp 3.0 to check for the possibility of oral delivery. In silico prediction of LD50 values were performed using Pro-Tox webserver. Interestingly, it was found that conjugation with amino acids decreases toxicity and increases the therapeutic index of thiosemicarbazide. Finally, all the compounds were docked to the crystal structure of the Vascular Endothelial Growth Factor Receptor-2 and Checkpoint kinase-1 utilizing Glide 5.0, Schrodinger 8.5, to understand the interaction of ligands with the receptor. A significant number of derivatives have been found active in both the receptors and also displayed multikinase inhibitory activity similar to Sorafenib, against hepatocellular carcinoma. Further, wet lab synthesis, in vitro ADMET and biological screening studies need to be performed to prove that designed compounds are effective against hepatocellular carcinoma as predicted by molecular modeling. However, as predicted by molecular modeling, the efficacy of designed compounds against hepatocellular carcinoma, needs to be confirmed by wet lab synthesis, in vitro ADMET and biological screening studies.