In silico discovery of dual-targeting molecules from Acalypha wilkesiana against hypertension and hyperglycemia

Hypertension and hyperglycemia are major risk factors for cardiovascular diseases and diabetes, necessitating the discovery of novel therapeutics targeting Human Endothelial Nitric Oxide Synthase (eNOS) and Glucagon-Like Peptide-1 Receptor (GLP-1R). Plant-derived phytochemicals have garnered attention for their potential to modulate these targets, prompting the investigation of A. wikesiana variants. This study employed gas chromatography-mass spectrometry (GC–MS) and computational simulations to investigate the phytochemical profile and potential bioactive properties of A. wikesiana variants. GC–MS analysis revealed distinct variations in phytochemical composition among pink, red, brown, and orange A. wikesiana leaf extracts, with sesquiterpenes prevalent in red and brown variants and monoterpenes dominating pink and orange leaves. Molecular docking simulations revealed indazol-4-one, 3,6,6-trimethyl-1-phthalazin-1-yl-1,5,6,7-tetrahydro- (ITPT) from the brown variant and 5.alpha.-cholest-8-en-3-one (5-ACE), from the orange variant, exhibited potent dual-targeting activity against eNOS and GLP-1R receptors. ITPT demonstrated a favourable pharmacokinetic profile, whereas 5-ACE exhibited excessive lipophilicity (log P = 7.07). Molecular dynamics simulation results confirmed ITPT's stable binding to eNOS and GLP-1R, characterized by low RMSD values of 1.6 Å and 1.0 Å, respectively, indicating a favourable receptor-ligand interaction. These results suggest that ITPT holds promise as a dual-targeting therapeutic agent for the simultaneous management of hypertension and hyperglycemia, warranting further investigation into its therapeutic potential.