title: Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth.
abstract: Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, and it is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Among a series of tested compounds, we have recently identified five synthetic chalcones which inhibit the activity of M. tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity. Kinetic studies demonstrated that these compounds are reversible competitive inhibitors. In this work we also carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target, PtpA, through molecular modeling. We observed that the predominant determinants responsible for the inhibitory activity of the chalcones are the positions of the two methoxyl groups at the A-ring, that establish hydrogen bonds with the amino acid residues Arg17, His49, and Thr12 in the active site of PtpA, and the substitution of the phenyl ring for a 2-naphthyl group as B-ring, that undergoes pi stacking hydrophobic interaction with the Trp48 residue from PtpA. Interestingly, reduction of mycobacterial survival in human macrophages upon inhibitor treatment suggests their potential use as novel therapeutics. The biological activity, synthetic versatility, and low cost are clear advantages of this new class of potential tuberculostatic agents.
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia
authors.forename: Javier
authors.initials: J
authors.lastname: Vernal
authors.forename: Andrea
authors.initials: A
authors.lastname: Villarino
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.forename: Paulo
authors.initials: P
authors.lastname: Perizzolo
authors.forename: Valerie
authors.initials: V
authors.lastname: Poirier
authors.forename: Dennis
authors.initials: D
authors.lastname: Wong
authors.forename: Priscila Graziela Alves
authors.initials: PG
authors.lastname: Martins
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Adriano Defini
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
authors.forename: Hernán
authors.initials: H
authors.lastname: Terenzi
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D047188:Chalcones; D017027:Protein Tyrosine Phosphatases