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

Abstract

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.

Pharmacophore-Based Virtual Screening Toward the Discovery of Novel Anti-echinococcal Compounds

“…Virtual screening has effectively shortened drug development time, reduced costs and improved efficiency, which can be very useful for the development of drugs to treat diseases that do not attract the attention of pharmaceutical companies. In recent years, computer-aided drug design has been applied to the discovery of anti-parasitic drugs (Postigo et al, 2010;Dube et al, 2012;Zhao et al, 2012;Pavadai et al, 2016;Vyas et al, 2016;Kagami et al, 2017;Araujo et al, 2018). Our study also indicated that virtual screening technology could play an important role in drug discovery for the treatment of echinococcosis.…”

“…Moreover, computer-aided drug design has been applied to the discovery of anti-parasitic drugs. Using pharmacophore-based virtual screening and molecular dynamics and molecular docking approaches, promising drug targets and hits are identified (Pavadai et al, 2016;Vyas et al, 2016;Kagami et al, 2017;Araujo et al, 2018). Among the predicted active compounds, some were shown to have anti-malarial activities in vitro and in vivo (Pavadai et al, 2016;Vyas et al, 2016).…”

Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies

“…Additionally, the number and permanence of hydrogen bonds in the complexes were calculated using the g_hbond module, implemented in the GROMACS 5.1.2 package and the HbMap2Grace program ( , accessed on 5 July 2021). The hydrogen bonds that showed a distance between the donor and acceptor that was lower than or equal to 3.5 Å and an angle between the donor/acceptor and the H atom that was lower than or equal to 60° were identified, as well as the bonds whose permanence time was lower than 10% of the total simulation time [ 58 ].…”