INVESTIGADORES
CORVI maria Martha
congresos y reuniones científicas
Título:
High throughput virtual screening reveals a promising specific inhibitor of Toxoplasma gondii N-myristoyltransferase
Autor/es:
ALONSO, AM; CORVI, MM; BUSTOS, DM
Lugar:
Mar del Plata
Reunión:
Congreso; X Congreso de protozoologia y enfermedades infecciosas; 2014
Institución organizadora:
Sociedad Argentina de Protozoologia
Resumen:
N-myristoyltransferase (NMT) is a
monomeric enzyme that catalyzes the covalent addition of myristate (C14:0
saturated fatty acid) onto proteins. This co- and post-translational modification
affects a variety of proteins, many of them important for the life-cycle of
cells, and influences different features such as localization, protein-protein
interaction and function. Protein
myristoylation is essential for cell viability and its peptide recognition
sites are species-specific, which makes it an ideal drug target for different
pathogens like fungi and protozooan parasites.
In this work we performed a bioinformatic analysis
that revealed that Toxoplasma gondii
genome encodes for a putative NMT which contains the N- and C-terminal domains characteristic
of the NMT family. Furthermore, primers designed for the T. gondii NMT coding sequence (CDS) published in the ToxoDB let us determine
that NMT is expressed in the T. gondii
RH strain.
In parallel, a
virtual screening (VS) on T. gondii
NMT (TgNMT) was performed using over 5000 compounds filtered from the ZINC
database. Since the crystal structure of TgNMT is not available, we created a
homology model to run the VS. The analysis resulted in 10 compounds with a high
predicted inhibition constant (Ki) over TgNMT, but only one of them was more
specific for TgNMT than that of the host NMT (hNMT). Interaction analysis of
the compound with TgNMT allowed us to infer that this compound might interact with
the peptide binding site of the enzyme, a site that has been described to be
species-specific. Besides, the compound interacts with the myristoil-CoA
binding site of the hNMT, which is conserved along different species, but the interaction
of the compound with hNMT was found to be a hundred times lower than with
TgNMT. These preliminary results are the first report on specific TgNMT
inhibitors and the starting point for the study of treatments designed
specifically for toxoplasmosis.