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Title: Evaluating Iso-Mukaadial Acetate and Ursolic Acid Acetate as Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase Inhibitors
Authors: Opoku, Francis
Govender, Penny P.
Pooe, Ofentse J.
Simelane, Mthokozisi B.C.
Keywords: Plasmodium falciparum
ursolic acid acetate
iso-mukaadial acetate
Issue Date: 2019
Publisher: MDPI
Citation: MDPI
Abstract: To date, Plasmodium falciparum is one of the most lethal strains of the malaria parasite. P. falciparum lacks the required enzymes to create its own purines via the de novo pathway, thereby makingPlasmodiumfalciparumhypoxanthine-guanine-xanthinephosphoribosyltransferase(PfHGXPT) a crucial enzyme in the malaria life cycle. Recently, studies have described iso-mukaadial acetate and ursolicacidacetateaspromisingantimalarials. However,themodeofactionisstillunknown,thus,the currentstudysoughttoinvestigatetheselectiveinhibitoryandbindingactionsofiso-mukaadialacetate and ursolic acid acetate against recombinant PfHGXPT using in-silico and experimental approaches. RecombinantPfHGXPTproteinwasexpressedusingE.coliBL21cellsandhomogeneouslypurifiedby affinity chromatography. Experimentally, iso-mukaadial acetate and ursolic acid acetate, respectively, demonstrated direct inhibitory activity towards PfHGXPT in a dose-dependent manner. The binding affinity of iso-mukaadial acetate and ursolic acid acetate on the PfHGXPT dissociation constant (KD), where it was found that 0.0833 µM and 2.8396 µM, respectively, are indicative of strong binding. The mode of action for the observed antimalarial activity was further established by a molecular docking study. The molecular docking and dynamics simulations show specific interactions and high affinity within the binding pocket of Plasmodium falciparum and human hypoxanthine-guanine phosphoribosyl transferases. The predicted in silico absorption, distribution, metabolism and excretion/toxicity (ADME/T) properties predicted that the iso-mukaadial acetate ligand may follow the criteria for orally active drugs. The theoretical calculation derived from ADME, molecular docking and dynamics provide in-depth information into the structural basis, specific bonding and non-bondinginteractionsgoverningtheinhibitionofmalarial. Takentogether,thesefindingsprovide a basis for the recommendation of iso-mukaadial acetate and ursolic acid acetate as high-affinity ligands and drug candidates against PfHGXPT.
Description: This article is published at MDPI and also available at, https://doi:10.3390/biom9120861
URI: doi:10.3390/biom9120861
Appears in Collections:College of Science

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