IMASL   20939
INSTITUTO DE MATEMATICA APLICADA DE SAN LUIS "PROF. EZIO MARCHI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Inhibitors of dihydrofolate reductase: a molecular dynamics study
Autor/es:
RODRIGO D. TOSSO; SEBASTIAN A. ANDUJAR; RODOLFO D. PORASSO
Lugar:
Tucumán
Reunión:
Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012
Institución organizadora:
SAB
Resumen:
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Dihydrofolate
reductase (DHFR) is the enzyme responsible for reducing dihydrofolic
acid to tetrahydrofolic acid. This enzyme is present in mammals,
protozoa, bacteria and fungi, but its structure is different in
different organisms, showing their different sensitivity to
inhibitors, which makes it an excellent target for the development of anticancer, antibacterial and more
specific and effective antiprotozoal drugs.
Previous studies
have established that inhibition of DHFR is a mechanism for drug
action(1-3).
Among the most popular clinical agents are methotrexate(4),
pyrimethamine(5-6) and
trimethoprim(7).
Methotrexate is a known inhibitor used as a selective anticancer drug
and the other two are used in antibacterial therapy (in the case of
trimethoprim as a broad antibacterial spectrum of action).
In
the present work we studied the binding of two series of
inhibitors by
molecular dynamics simulation, a
series called RRA_XXX which have a pyrimidine nucleus and RRA_XXXA
which have a purine nucleus.
To this end we used umbrella sampling to determine the potential of
mean force to predict the relative free energy of binding of these
inhibitors. We found that the relative free energy range is between
40 and
140 kJ.mol-1,
these values agrees excellent with the trend of the experimental
assays.