title: Novel Thiosemicarbazide Hybrids with Amino Acids and Peptides Against Hepatocellular Carcinoma: A Molecular Designing Approach Towards Multikinase Inhibitor.
abstract: 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, Schrödinger 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.
authors.forename: Shinu
authors.initials: S
authors.lastname: Chacko
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkand, Ranchi-835215, India..
authors.forename: Subir
authors.initials: S
authors.lastname: Samanta
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D012663:Semicarbazides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000596:Amino Acids; D010455:Peptides; D047428:Protein Kinase Inhibitors; D012663:Semicarbazides; C005151:thiosemicarbazide; D011494:Protein Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1