title: Discovering Echinococcus granulosus thioredoxin glutathione reductase inhibitors through site-specific dynamic combinatorial chemistry.
abstract: In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine (2af) was identified, upon library analysis by HPLC (IC50 = 24 μM). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure-activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine (2aj) as the best enzyme inhibitor in these series, with an IC50 = 24 μM. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases.
authors.affiliation: Cátedra de Química Farmacéutica, Facultad de Química, Universidad de la República (UdelaR), Gral. Flores 2124, 1157 , Montevideo, Uruguay.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Saiz
authors.forename: Valerie
authors.initials: V
authors.lastname: Castillo
authors.forename: Pablo
authors.initials: P
authors.lastname: Fontán
authors.forename: Mariana
authors.initials: M
authors.lastname: Bonilla
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salinas
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodríguez-Haralambides
authors.forename: S Graciela
authors.initials: SG
authors.lastname: Mahler
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D019281:Dimerization; D055808:Drug Discovery; D048209:Echinococcus granulosus / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009579:Nitrobenzoates / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009579:Nitrobenzoates; D054852:Small Molecule Libraries; D013438:Sulfhydryl Compounds; D053778:Thiazolidines; C011136:thionitrobenzoic acid; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase