Interactions of Pyrimidine Derivatives with Dihydrofolate Reductase and Thymidylate Synthase: Directions Toward Combating toxoplasmosis

Letícia   C.   Assis; Letícia      Santos-Garcia; Teodorico   C.   Ramalho; Elaine   F. F. da   Cunha

Abstract

Toxoplasma gondii (T. gondii) is the most common cause of secondary central nervous system infection in immunocompromised persons such as AIDS patients. Dihydrofolate reductase and thymidylate synthase enzymes have been studied as attractive targets against parasitic diseases, since they are involved in cell proliferation and influence on DNA synthesis. In this paper, we propose three-dimensional structures of T. gondii dihydrofolate reductase and thymidylate synthase based on homology modeling. In addition, we assessed the interaction mode of pyrimidine analogs in the active site of T. gondii and human enzymes, in order to direct the planning of new compounds that can be used against toxoplasmosis. According to the docking studies, predicted pIC50 values for proposed compounds were higher than those of the experimentally most active compound.

Keywords: Molecular modeling, toxoplasmosis, dihydrofolate reductase and thymidylate synthase.