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

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 861
Author(s):  
Francis Opoku ◽  
Penny P. Govender ◽  
Ofentse J. Pooe ◽  
Mthokozisi B.C. Simelane
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Ursolic Acid ◽  
Mode Of Action ◽  
In Silico ◽  
Structural Basis ◽  
Depth Information ◽  
Dependent Manner ◽  
High Affinity ◽  
Molecular Docking And Dynamics

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.

scholarly journals Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

2019 ◽  
Vol 13 ◽  
pp. 117793221986553 ◽  
Author(s):  
Gbolahan O Oduselu ◽  
Olayinka O Ajani ◽  
Yvonne U Ajamma ◽  
Benedikt Brors ◽  
Ezekiel Adebiyi
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
In Silico ◽  
Homology Modelling ◽  
3D Structure ◽  
Docking Studies ◽  
Binding Energies ◽  
Benzimidazole Derivatives ◽  
Adenylosuccinate Lyase ◽  
In Silico Admet

Plasmodium falciparum adenylosuccinate lyase ( PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[ d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from −6.85 to −8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

scholarly journals Augmented Cell Signaling by Betanin insights Cancer Cell Remodeling: A Molecular Docking and Experimental Approach

2021 ◽  
Vol 12 (3) ◽  
pp. 3161-3172
Keyword(s):  
Cell Cycle ◽  
Molecular Docking ◽  
Cancer Cell ◽  
In Silico ◽  
Topoisomerase I ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Dna Topoisomerase ◽  
Docking Analysis

Molecular docking analysis has shown to be an important tool for systematically harnessing natural pigment betanin's structural diversity. Natural betanin pigment was used to investigate its anticancer efficacy by in vitro cytotoxicity and cell cycle analysis in A549 lung cancer cell line. Furthermore, docking analysis was used to determine the promising molecular targets for the betanin using different receptor proteins and enzymes responsible for DNA replication (DNA topoisomerases I and II), cell cycle (CDK-6), and in silico apoptotic markers (Bcl-2 and caspase-3) using Glide Schrodinger. In vitro analysis revealed that betanin exerts cytotoxic effects in a cancer cell by inducing apoptosis in a dose-dependent manner with an IC50 value of 17 µM. Furthermore, the cell cycle arrest in response to betanin treatment was strongly observed in flow cytometry analysis. The in silico docking results revealed that betanin exhibited splendid interaction with high affinity against the CDK-6, Bcl-2, and caspase-3 with superior docking scores. Betanin was best docked with DNA topoisomerase II than DNA topoisomerase I. Overall, our report provides scientific evidence that betanin is a novel drug moiety with anticancer property attributes that might be developed and formulated as drug candidate/lead compounds for cancer chemotherapy.

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