title: Identification of potential transmembrane protease serine 4 inhibitors as anti-cancer agents by integrated computational approach.
abstract: Transmembrane protease serine 4 is a well known cell surface protease facilitating the extracellular matrix degradation and epithelial mesenchymal transition in hepatocellular carcinoma. Henceforth targeting transmembrane protease serine 4 is strongly believed to provide therapeutic intervention against hepatocellular carcinoma. Owing to lack of crystal structure for human transmembrane protease serine 4, we predicted its three dimensional structure for the first time in this study. Experimentally proven inhibitor-Tyroserleutide (TSL) against hepatocellular carcinoma via transmembrane protease serine 4 was used as a benchmark to identify structurally similar candidates from PubChem database to create the TSL library. Virtual screening of TSL library against modeled transmembrane protease serine 4 revealed the top four potential inhibitors. Further binding free energy (ΔGbind) analysis of the potential inhibitors revealed the best potential lead compound against transmembrane protease serine 4. Drug likeliness nature of the top four potential hits were additionally analyzed in comparison to TSL to confirm on the best potential lead compound with the highest % of human oral absorption. Consequently, e-pharmacophore mapping of the best potential lead compound yielded a six point feature. It was observed to contain four hydrogen bond donor sites (D), one positively ionizable site (P) and one aromatic ring (R). Such e-pharmacophore insight obtained from structural determinants by integrated computational analysis could serve as a framework for further advancement of drug discovery process of new anti-cancer agents with less toxicity and high specificity targeting transmembrane protease serine 4 and hepatocellular carcinoma.
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India.
authors.forename: M
authors.initials: M
authors.lastname: Ilamathi
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India.
authors.forename: R
authors.initials: R
authors.lastname: Hemanth
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India.
authors.forename: S
authors.initials: S
authors.lastname: Nishanth
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, India. Electronic address: sivaramakrishnan@scbt.sastra.edu.
authors.forename: V
authors.initials: V
authors.lastname: Sivaramakrishnan
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012694:Serine / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry*; D012984:Software
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D008024:Ligands; D008565:Membrane Proteins; D012694:Serine; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: E-pharmacophore; Hepatocellular carcinoma; Inhibitors; Tyroserleutide; Virtual screening