Estudo de modelagem molecular de derivados de desoxiuridina como inibidores da dUTPase de Plasmodium falciparum.

Abstract

Malaria is a parasitic disease that continues to b e responsible for a huge number of deaths around the world. The disease is p resent in 99 countries with the alarming number of deaths per year reaching 655,000 ; about 3.3 billion people are at risk areas. Among the agents that cause malaria, Plasmodium falciparum causes the most severe cases, being responsible for about 90% of deaths from this disease. Currently available treatments include the drugs ch loroquine, primaquine, artemisinin and lumefantrine. However, due to its indiscriminat e use for years, parasite resistance to these treatments has become a big pro blem. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) of Plasm odium falciparum (EC 3.6.1.23) was chosen as the molecular target for th is study. We produced a complete structural model of Pf dUTPase (PDB ID: 1VYQ) by homology modeling, since the crystal structure stored in the Protein Data Bank s hows regions of undetermined conformation. In this work we used, in addition to conventional molecular dynamics, the Steered Molecular Dynamics technique to simulat e the unbinding process of four deoxyuridine derivatives acting as Pf dUTPase inhibitors. For this purpose, we adopted the external steering force of 0,2 kcal/mol /Å 2 at a constant velocity of 0,02 Å/ps. Hydrogen bonds are formed between the ligand and the residue Ile117 up to 90% of the trajectory. The water molecule of the ac tive site obtained Hbond results up to 68%. The force profiles of the SMD calculatio ns showed linear correlation coefficient R 2 of 0.96 with the Ki experimental data. Our results show quantitatively that the residue Ile117 is the main responsible for the anchoring of the ligands in the active site.