title: Pharmacophore-based screening and identification of novel human ligase I inhibitors with potential anticancer activity.
abstract: Human DNA ligases are enzymes that are indispensable for DNA replication and repair processes. Among the three human ligases, ligase I is attributed to the ligation of thousands of Okazaki fragments that are formed during lagging strand synthesis during DNA replication. Blocking ligation therefore can lead to the accumulation of thousands of single strands and subsequently double strand breaks in the DNA, which is lethal for the cells. The reports of the high expression level of ligase I protein in several cancer cells (versus the low ligase expression level and the low rate of division of most normal cells in the adult body) support the belief that ligase I inhibitors can target cancer cells specifically with minimum side effects to normal cells. Recent publications showing exciting data for a ligase IV inhibitor exhibiting antitumor activity in mouse models also strengthens the argument for ligases as valid antitumor targets. Keeping this in view, we performed a pharmacophore-based screening for potential ligase inhibitors in the Maybridge small molecule library and procured some of the top-ranking compounds for enzyme-based and cell-based in vitro screening. We report here the identification of novel ligase I inhibitors with potential anticancer activity against a colon cancer cell line.
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.forename: Deependra Kumar
authors.initials: DK
authors.lastname: Singh
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Meena
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Banerjee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000607892:LIG1 protein, human; C022262:Okazaki fragments; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP