Translational Insight into Gongronema latifolium-silver Nanoparticles: Linking in vivo Safety to Molecular Antimalarial Mechanism

Abstract

Building upon our recent finding that the biopolymer matrix of green-synthesized silver nanoparticles (AgNPs) dictates their exceptional safety (LD50 > 5000 mg/kg) and antimalarial efficacy, this study employed a computational framework to de-convolute the molecular identity of this critical passivation layer. While our previous in vivo work hypothesized that the organic capping matrix facilitates endocytic uptake and mitigates toxicity, the specific ligand-receptor interactions remained undefined. In the present study, we utilized Density Functional Theory (DFT), ADMET profiling, and MM-GBSA calculations to interrogate the primary Gongronema latifolium phytochemicals constituting the nanoparticle surface. DFT analysis confirmed the structural hypothesis: Sarsasapogenin served as the rigid, chemically inert steric stabilizer (\(\Delta\)Egap= 8.83 eV), explaining the protective masking observed previously in XRD, while Tannic Acid (\(\Delta\)Egap = 2.91 eV) drives the redox activity. Pharmacokinetic screening identified Cinchonidine as the bioactive lead, with 94.5% oral bioavailability and blood-brain barrier permeability. Crucially, molecular docking revealed that this biopolymer complex does not merely act via general oxidative stress; Cinchonidine selectively targets Plasmodium falciparum Dihydrofolate Reductase (PfDHFR; \(\Delta\)Gbind = -48.85 kcal/mol) while sparing Lactate Dehydrogenase (PfLDH). These findings provide the molecular validation for our prior empirical observations, bridging the gap between murine safety signals and human therapeutic mechanisms.