Antiplasmodial Activity of Methylangolensate From Entandrophragma angolense (Welw.) C.DC. Stem Bark: An In Vitro and...

Previous investigation of the antiplasmodial effects of methylangolensate (MAL) has revealed promising activity against multiple strains of Plasmodium falciparum parasites. However, a significant gap still remains to be bridged regarding its potential as a lead compound for the development of novel drugs for the treatment of malaria. The study seeks to evaluate the multistage antiplasmodial effects, drug likeness, in silico ADMET properties, and possible drug targets of MAL against the P. falciparum parasites.

The cytotoxic effects of MAL on HepG2 cells and the inhibitory effects of MAL against the blood stages of both 3D7 P. falciparum and Dd2 P. falciparum were assessed using a tetrazolium-based colorimetric test and SYBR Green assay, respectively. The nature of the interactions between MAL and some validated drug targets of malaria (DHFR-TS, PfLDH, FP-2, plasmepsins II, PfDHODH and PfHGXPRT) were determined using molecular docking and molecular dynamics simulations. The drug likeness of MAL was predicted using rule-based filters such as Lipinski. The ADMET properties of MAL were predicted using the SwissADME online tool. A modified in vitro antiplasmodial method involving the supplementation of the culture media with varying concentrations of folic acid was used to validate the antifolate potential of MAL.

MAL demonstrated minimal cytotoxic effects (CC₅₀ of 89.39 μg/mL) against HepG2 liver cells. MAL demonstrated a good antiplasmodial effect against the trophozoites and schizonts (IC₅₀ of 0.8568-5.1210 μg/mL) and moderate gametocytocidal activity (IC₅₀ of 12.0800-18.8200 μg/mL) against both 3D7 P. falciparum and Dd2 P. falciparum parasites. MAL met all the criteria set by Lipinski, Ghose, Veber, and Abbott bioavailability score for a drug-like compound and had favorable predicted ADMET properties. The compound demonstrated a strong affinity for the active sites of DHFR-TS, PfLDH main pocket, PfLDH cofactor active site, falcipain-2, plasmepsins II, PfDHODH, and PfHGXPRT with binding energies of -10.54, -7.25, -8.05, -7.77, -7.39, -9.41, and -8.02 Kcal/mol, respectively. Molecular dynamics simulation revealed stable docked MAL-protein complexes. MAL showed good potential as an antifolate agent.

MAL may serve as a lead compound for the design and development of novel drugs that elicit their antiplasmodial effects by interfering with folate metabolism, DNA synthesis, energy metabolism, and nutrition of the P. falciparum parasites.