Andrographolide from Andrographis paniculata as a potential inhibitor of the novel malarial drug target PF11_0189: a comprehensive in silico approach

Malaria caused by Plasmodium falciparum still claims more than 600,000 lives every year, and the spread of partial artemisinin resistance across South and Southeast Asia now threatens the only first-line therapy available, making antimalarials with genuinely new mechanisms of action an urgent global priority. PF11_0189, an essential M16 insulinase-family metallopeptidase of P. falciparum with no significant human homolog, is a validated yet pharmacologically unexploited drug target. Here we combine the ethnopharmacological heritage of Northeast India (where Andrographis paniculata (Kalmegh) is the most consistently documented antimalarial herb across twelve tribal communities) with a statistically validated, multi-layered computational pipeline to identify putative PF11_0189 inhibitors in silico. Docking of ten A. paniculata phytochemicals, benchmarked against property-matched decoys (ROC-AUC = 0.81; enrichment factor at 1% = 12.4), ranked andrographolide as the top hit, outscoring the reference antimalarial chloroquine by 1.5 kcal/mol (− 8.4 vs. − 6.9 kcal/mol). Andrographolide paired a clean, alert-free drug-likeness profile (zero Lipinski violations; non-hERG; non-P-glycoprotein substrate; PAINS/Brenk-negative) with triplicate 100-ns molecular dynamics simulations that indicated a stable complex (backbone RMSD < 2.5 Å), a single dominant free-energy minimum, and a binding free energy of − 42.3 kJ/mol anchored by five energetic hotspot residues (Glu-203, Thr-89, Phe-116, Trp-214, Ser-112) independently corroborated by hydrogen-bonding and cross-correlation analyses. This convergence of five independent computational lines of evidence nominates andrographolide as a computationally prioritised, mechanistically testable candidate inhibitor of PF11_0189 and provides a hotspot-guided blueprint for structure-based antimalarial development. This is a purely computational study without wet-lab validation: the receptor is an AlphaFold2 model, and enzyme-inhibition, biophysical binding and in vitro antiplasmodial assays are still required before andrographolide can be considered a validated PF11_0189 inhibitor.