Identification of new promising Plasmodium falciparum superoxide dismutase allosteric inhibitors through hierarchical pharmacophore-based virtual screening and molecular dynamics.

Malaria is the world's most widespread protozoan infection, being responsible for more than 445,000 annual deaths. Among the malaria parasites, Plasmodium falciparum is the most prevalent and lethal. In this context, the search for new antimalarial drugs is urgently needed. P. falciparum superoxide dismutase (PfSOD) is an important enzyme involved in the defense mechanism against oxidative stress. The goal of this study was to identify through hierarchical screening on pharmacophore models and molecular dynamics (MD), promising allosteric PfSOD inhibitors that do not show structural requirements for human inhibition. MD simulations of 1000 ps were performed on PfSOD using GROMACS 5.1.2. For this, the AMBER99SB-ILDN force field was adapted to describe the metal-containing system. The simulations indicated stability in the developed system. Therefore, a covariance matrix was generated, in which it was possible to identify residues with correlated and anticorrelated movements with the active site. These results were associated with the results found in the predictor of allosteric sites, AlloSitePro, which affirmed the ability of these residues to delimit an allosteric site. Then, after successive filtering of the Sigma-Aldrich® compounds database for HsSOD1 and PfSOD pharmacophores, 152 compounds were selected, also obeying Lipinski's rule of 5. Further filtering of those compounds based on molecular docking results, toxicity essays, availability, and price filtering led to the selection of a best compound, which was then submitted to MD simulations of 20,000 ps on the allosteric site. The study concludes that the ZINC00626080 compound could be assayed against SODs. Graphical Abstract Plasmodium falciparum superoxide dismutase.