Structural prioritization of Andrographis paniculata diterpenoids at the interface between PCSK9 and LDLR

Proprotein convertase subtilisin/kexin type 9 (PCSK9) engages the epidermal growth factor-like repeat A of the low-density lipoprotein receptor (LDLR) through a broad, solvent-exposed protein-protein interface, making structural complementarity more informative than docking score alone. Six Andrographis paniculata diterpenoids were compared by triplicate seeded AutoDock Vina docking against the PCSK9-LDLR interface, prospective mapping of 19 PCSK9 contact residues, physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, receptor-model qualification, and matched 1 ns molecular-dynamics simulations of the affinity-ranked isoandrographolide (L05) and interface-ranked andrograpanin (L06) complexes. Median docking affinities spanned only − 5.6 to − 6.3 kcal mol-1. L05 gave the most favorable median score (− 6.3 kcal mol-1), whereas L06 reproducibly occupied a broader recognition footprint involving SER153, PRO155, ASP238, ALA239, ILE369, PHE379, VAL380, and SER381. The sequence-verified PCSK9 153–446 model retained low short-timescale backbone fluctuations. In matched simulations, L06 showed lower protein-aligned ligand root-mean-square deviation (RMSD) than L05 (0.0961 vs. 0.1355 nm), a higher proportion of frames containing at least one hydrogen bond (58.4% vs. 47.5%), and broad residue-level occupancy across proximal, central, and distal LDLR-recognition segments during the sampled interval. These observations distinguish affinity ranking from short-timescale interface engagement and prioritize andrograpanin for interface-directed experimental testing. Because the trajectories were 1 ns, unreplicated, and not designed to establish convergence, residue occupancy and hydrogen-bond frequencies are descriptive of the sampled trajectories; no binding free-energy or biochemical measurements were obtained. The findings therefore represent structure-based prioritization rather than evidence of PCSK9-LDLR inhibition.