title: An antiarrhythmic agent as a promising lead compound for targeting the hEAG1 ion channel in cancer therapy: insights from molecular dynamics simulations.
abstract: Experimental evidence suggests that hERG and hEAG potassium channels may serve as important cancer therapy targets because either of the channel blockade or inactivation by different methods leads to inhibition of cancer cells growth and proliferation. However, there is no known hEAG specific blocker, and hERG blockade leads to adverse cardiac side effects, although it is currently used in treating certain types of arrhythmias. There have been some attempts to explain the channels blockade by clofilium, an antiarrhythmic agent, and the results lead to different possible binding modes. This study investigates for the first time the potential of using clofilium as a lead compound for finding a novel cancer therapy agent which may target ion channels. The implied findings from a comparative assessment of literature studies were verified using molecular dynamics simulations. The results indicate a particular structural difference between the two channels that could provide a novel and realistic way of using clofilium analogs which may target the hEAG1 ion channel in cancer therapy.
authors.affiliation: Department of Biology, Biophysics Laboratory, Alexandru Ioan Cuza University, Iași, Romania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Șterbuleac
authors.affiliation: Department of Biology, Biophysics Laboratory, Alexandru Ioan Cuza University, Iași, Romania. cmaniu@uaic.ro.
authors.forename: Călin Lucian
authors.initials: CL
authors.lastname: Maniu
mesh_terms: D000595:Amino Acid Sequence; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D000644:Quaternary Ammonium Compounds; C022799:clofilium
keywords: cancer; drug targeting; hEAG; hERG; molecular dynamics; molecular modeling; protein structure