Homology Modeling and Docking Mechanism of the Mercaptosuccinate and Methotrexate to P. falciparum 1-Cys Peroxiredoxin: A Preliminary Molecular Study

Abstract

A three-dimensional (3-D) model of 1-Cys peroxiredoxin from P. falciparum (Pf-Prx) has been constructed by homology modeling. The model building was based on a structural alignment with the human 1-Cys peroxiredoxin X-ray structure. First, mercaptosuccinate was docked by Molecular and Quantum Mechanics at the active site in both isozymes, evidencing the role of different residues in the ligand-protein interaction. Stable conformation of the inhibitor in the active site was obtained from the conformational analysis by molecular dynamics. Next, The complex was reoptimized by semiempirical molecular orbital AM1 method. Conformational and frontier orbitals analyses of the ligand-protein complex were carried out in an attempt to obtain structural insight into the inhibition mechanism.

Finally, the docking study of the methotrexate (MTX), an anticancer drug also used as an antimalarial inhibitor, into the model's binding site was performed. From the resulting stable complex structure, it was found that the glutamate ring of MTX fits the active site with high complementarity. The glutamate ring formed two hydrogen bonds to the imidazol group of His41 and the amino groups of Arg129. The side-chain of glutamate was in close proximity to the sulfur atom of the catalytic residue, Cys47. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue is covered with the glutamate ring of the MTX inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies and the molecular orbitals localization between the Pf-Prx active site and the inhibitors alluded to the probable binding sites of the ligand nucleophilic ring.