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.
Highlights
Even though great strides have been taken to control malaria over the past decade, it is still regarded as a major public health problem across the globe [1]
It is estimated that 25% of drugs are derived from plants [3], investigating these compounds could possibly lead to the discovery of more potent drugs that could be used against malaria parasites
We describe for the first time the direct inhibitory role of iso-mukaadial acetate (IMA) and ursolic acid acetate (UAA) on Pf HGXPRT using computational and various wet-lab approaches
Summary
Even though great strides have been taken to control malaria over the past decade, it is still regarded as a major public health problem across the globe [1]. It is estimated that 25% of drugs are derived from plants [3], investigating these compounds could possibly lead to the discovery of more potent drugs that could be used against malaria parasites. We investigated Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (Pf HGXPRT), an essential malaria protein, as a potential target for iso-mukaadial acetate and ursolic acid acetate. The Plasmodium falciparum parasite lacks the necessary de novo pathway enzymes to create its own purines and is dependent upon the salvage pathway [6,7,8]. This difference can be exploited to design novel drugs to inhibit
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
