title: Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2).
abstract: Recent studies have revealed that compounds believed to be highly selective frequently address multiple target proteins. We investigated the protein interaction profile of the widely prescribed thrombin inhibitor dabigatran (1), resulting in the identification and subsequent characterization of an additional target enzyme. Our findings are based on an unbiased functional proteomics approach called capture compound mass spectrometry (CCMS) and were confirmed by independent biological assays. 1 was shown to specifically bind ribosyldihydronicotinamide dehydrogenase (NQO2), a detoxification oxidoreductase. Molecular dockings predicted and biological experiments confirmed that dabigatran ethyl ester (2) inhibits NQO2 even more effectively than the parent 1 itself. Our data show that 1 and 2 are inhibitors of NQO2, thereby revealing a possible new aspect in the mode of action of 1. We present a workflow employing chemical proteomics, molecular modeling, and functional assays by which a compound's protein-interaction profile can be determined and used to tune the binding affinity.
authors.affiliation: caprotec bioanalytics GmbH, Volmerstrasse 5, 12489 Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Michaelis
authors.forename: Anett
authors.initials: A
authors.lastname: Marais
authors.forename: Anna K
authors.initials: AK
authors.lastname: Schrey
authors.forename: Olivia Y
authors.initials: OY
authors.lastname: Graebner
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schaudt
authors.forename: Michael
authors.initials: M
authors.lastname: Sefkow
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kroll
authors.forename: Mathias
authors.initials: M
authors.lastname: Dreger
authors.forename: Mirko
authors.initials: M
authors.lastname: Glinski
authors.forename: Hubert
authors.initials: H
authors.lastname: Koester
authors.forename: Rainer
authors.initials: R
authors.lastname: Metternich
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Fischer
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D000069604:Dabigatran; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D013058:Mass Spectrometry; D008956:Models, Chemical; D011485:Protein Binding; D040901:Proteomics / Q000379:methods; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D013917:Thrombin / Q000037:antagonists & inhibitors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011725:Pyridines; D015091:beta-Alanine; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D013917:Thrombin; D000069604:Dabigatran; C573560:dabigatran ethyl ester