Inhibitors of Dihydrofolate reductase: a Molecular Dynamics Study

TOSSO, RODRIGO DAVID; ANDUJAR, SEBASTIAN; PORASSO, RODOLFO

San Javier - Tucumán

Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

ABSTRACT 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. Among the most popular clinical agents are methotrexate, pyrimethamine and trimethoprim. 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, one series called RRA_XXX have a pyrimidine nucleus and the other series RRA_XXXA 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 10 and 35 kCal/mol, these values agrees excellent with the trend of the experimental assays.