In silico identification of the anthraquinone pigment morindone as a Plasmodium Falciparum Lactate Dehydrogenase (PFLDH) inhibitory antimalarial drug lead

Abstract

Plasmodium falciparum Lactate Dehydrogenase (PfLDH) inhibition could be exploited for the purpose of fast parasitemia clearance necessary for the treatment and/or prevention of cerebral malaria (CM). This investigation was aimed at in silico evaluations of Morinda lucida-based anthraquinones for their potential PfLDH inhibitory activities via interference with the enzyme’s cofactor (NADH) redox function. Thirty-seven (37) anthraquinones of Morinda lucida were docked to the NADH-binding site of a ternary model of PfLDH. Considering -8.0 Kcal/mol binding affinity as comparable to the -10 Kcal/mol binding affinity of NADH, top nine of the docked ligands (binding energies -8.3Kcal/mol to -9.7 Kcal/mol) were initially selected as hits and subjected to drug-likeness screening using the five (Lipinski, Ghose, Verber, Egan and Muege) drug-likeness filters of the SwissADME webserver. Six of them, showing no violation of any of the stipulations of each of the five filters were subjected to toxicity profiling predictions with Protox II webserver, leading to the selection of morindone (Binding energy -8.4 Kcal/mol; predicted LD₅₀ 7000 mg/Kg) as the safest. Subsequent Molecular Dynamics (MD) simulations on morindone-PfLDH complex showed that both morindone and its PfLDH complex were stable over a 50 ns simulation, the RMSD-time plot of the complex showing a convergence of its initial and instantaneous structures at around 5 ns with deviations largely around 3 Å throughout the 50 ns simulation period. The Morinda lucida-based anthraquinone pigment morindone is hereby uncovered as a potential lead or template for the discovery of PfLDH inhibitory antimalarials deployable for the treatment of severe falciparum malaria and its cerebral malaria prognosis.