Evaluating Iso-Mukaadial Acetate and Ursolic Acid Acetate as Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase Inhibitors

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 making Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPT) a crucial enzyme in the malaria life cycle. Recently, studies have described iso-mukaadial acetate and ursolic acid acetate as promising antimalarials. However, the mode of action is still unknown, thus, the current study sought to investigate the selective inhibitory and binding actions of iso-mukaadial acetate and ursolic acid acetate against recombinant PfHGXPT using in-silico and experimental approaches. Recombinant PfHGXPT protein was expressed using E. coli BL21 cells and homogeneously purified by 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-bonding interactions governing the inhibition of malarial. Taken together, these findings provide a basis for the recommendation of iso-mukaadial acetate and ursolic acid acetate as high-affinity ligands and drug candidates against PfHGXPT.

Molecular Docking Study and Pharmacophore Modelling of Ursolic Acid as an Antimalarial Using Structure-Based Drug Design Method

“…The results showed that carbocyclic acid and hydroxyl were the main functional groups responsible to bond with the significant amino acid residues on each receptor, while hydrocarbon emerges as the potential component that can be modified in future drug development due to its unintended interaction with the amino acid residues. After doing a literature review about the effects of UA compounds on various targets from various diseases, we found that hydroxyl and carboxyl groups play a crucial role in the interaction of amino acids at the receptors; hence, we are in the same conclusions [7,23,24].…”

“…The UA acetate had strong binding affinities for the PfHGXPT and the dissociation constant (KD) reaching 2.8396 µM as reported in the study. The precise contacts and high affinities found in the binding pockets of human and PfHGXPT were demonstrated using molecular docking and dynamics simulations [7].…”

Evaluating the Antioxidant and Heavy Metal Content of Pleurotus ostreatus Mushrooms Cultivated using Sugar Cane Agro-Waste

“…Radicals such as hydroxyl radicals have the potential to damage DNA, lipids and proteins. 14,[33][34][35] Results on Figure 3 proved that exposing pET30 plasmid DNA to Fenton's reagent caused complete damage of plasmid DNA. This is due to hydroxyl radical since it reacts with nitrogen bases of DNA causing production of both base radicals and sugar radicals which then react and results in breakage of sugar phosphate leading to DNA damage.…”

<p>Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases</p>

“…19,20 The spread of multi-drug resistance in malaria treatment and the absence of new antimalarial compounds requires an urgent need for new drug regime for malaria, which kills 11 million people every year. [19][20][21][22] There is a growing interest in drug combinations as an alternative new treatment approach against malarial parasite. Azithromycin is a macrolide antibiotic that is particularly attractive as an antimalarial because of its safety in children.…”