Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity

Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere-Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.

Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions

“…Family 2 DHODHs are conserved in several pathogens such as Helicobacter pylori ( Copeland et al, 2000 ; Ohishi et al, 2018 ), those causing fungal infections ( Oliver et al, 2016 ; Wiederhold, 2017 ), Toxoplasma gondii ( Hortua Triana et al, 2016 ), and Plasmodium falciparum ( Singh et al, 2017 ). The ubiquinone binding site in P. falciparum DHODH ( Pf DHODH) is known to be significantly divergent from its human counterpart and several groups have reported on the discovery of parasite-specific DHODH inhibitors ( Booker et al, 2010 ; Wadood and Ulhaq, 2013 ; Xu et al, 2013 ; Kokkonda et al, 2016 ; Vyas et al, 2016 ; Azeredo et al, 2017 ; Maetani et al, 2017 ). Recently, Phase Ia/Ib studies of a potent and specific Pf DHODH inhibitor, DSM265, have been published with promising results ( McCarthy et al, 2017 ; Sulyok et al, 2017 ).…”

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).…”

“…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). Leucyl-tRNA synthetase and pteridine reductase of trypanosomatid parasites were used as potential targets for screening novel anti-trypanosomatid compounds, and new potential inhibitory scaffolds were predicted; however, further validation is needed (Dube et al, 2012;Zhao et al, 2012).…”

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation

“…V.K. Vyas et al [ 9 ] claimed that structure-based pharmacophore modeling, virtual screening, docking and biological evaluation are the rational strategies for the identification of novel hits or leads with diverse chemical scaffolds. In their studies, in silico ADMET prediction was also conducted.…”