title: A Biologically-Based Computational Approach to Drug Repurposing for Anthrax Infection.
abstract: Developing drugs to treat the toxic effects of lethal toxin (LT) and edema toxin (ET) produced byB. anthracisis of global interest.We utilized a computational approach to score 474 drugs/compounds for their ability to reverse the toxic effects of anthrax toxins. For each toxin or drug/compound, we constructed an activity network by using its differentially expressed genes, molecular targets, and protein interactions. Gene expression profiles of drugs were obtained from the Connectivity Map and those of anthrax toxins in human alveolar macrophages were obtained from the Gene Expression Omnibus. Drug rankings were based on the ability of a drug/compound's mode of action in the form of a signaling network to reverse the effects of anthrax toxins; literature reports were used to verify the top 10 and bottom 10 drugs/compounds identified. Simvastatin and bepridil with reported in vitro potency for protecting cells from LT and ET toxicities were computationally ranked fourth and eighth. The other top 10 drugs were fenofibrate, dihydroergotamine, cotinine, amantadine, mephenytoin, sotalol, ifosfamide, and mefloquine; literature mining revealed their potential protective effects from LT and ET toxicities. These drugs are worthy of investigation for their therapeutic benefits and might be used in combination with antibiotics for treatingB. anthracisinfection.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. jane.bai@fda.hhs.gov.
authors.forename: Jane P F
authors.initials: JP
authors.lastname: Bai
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. teo.sakel@gmail.com.|School of Mechanical Engineering, National Technical University of Athens, Zografou 15780, Greece. teo.sakel@gmail.com.
authors.forename: Theodore
authors.initials: T
authors.lastname: Sakellaropoulos
authors.affiliation: School of Mechanical Engineering, National Technical University of Athens, Zografou 15780, Greece. leo@mail.ntua.gr.
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Alexopoulos
mesh_terms: D000881:Anthrax / Q000188:drug therapy*; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D019295:Computational Biology; D058492:Drug Repositioning; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000931:Antidotes; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin
keywords: anthrax; computation; drug repurposing; signaling network of a drug