Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth.
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.
Mascarello
Alessandra
A
Departamento de Química, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil.
Chiaradia
Louise Domeneghini
LD
Vernal
Javier
J
Villarino
Andrea
A
Guido
Rafael V C
RV
Perizzolo
Paulo
P
Poirier
Valerie
V
Wong
Dennis
D
Martins
Priscila Graziela Alves
PG
Nunes
Ricardo José
RJ
Yunes
Rosendo Augusto
RA
Andricopulo
Adriano Defini
AD
Av-Gay
Yossef
Y
Terenzi
Hernán
H
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
D000995:Antitubercular Agents; D047188:Chalcones; D017027:Protein Tyrosine Phosphatases