Acanthus montanus Phytochemicals as Potential Multi-Target Therapeutics for Uterine Fibroids: An Integrated GC-MS, Network Pharmacology, and Molecular Dynamics Study

Abstract

Uterine fibroids are benign hormone-responsive tumours characterized by dysregulated cellular proliferation, extracellular-matrix accumulation, and altered growth-factor signaling. This study investigated the potential anti-fibroid activity of Acanthus montanus leaf phytochemicals using an integrated computational approach. Ethanolic leaf extract was subjected to GC–MS profiling, followed by ADME/drug-likeness screening, network pharmacology, molecular docking, 100-ns molecular dynamics (MD) simulation, PASS activity prediction, and toxicity assessment. GC–MS identified 20 putative phytoconstituents, with 2,3-bis[(4-hydroxy-3-methoxyphenyl)methyl]butane-1,4-diol, tetramethyl ether showing 95% spectral similarity. Fourteen compounds (70%) exhibited high predicted gastrointestinal absorption, while the prioritized tetramethyl ether derivative showed favourable drug-likeness and no PAINS alerts. Network pharmacology identified 25 overlapping targets associated with uterine fibroids, with enrichment of PI3K-Akt, MAPK, estrogen, hormone-related, and other proliferation-associated pathways. Molecular docking showed that leuprolide had SP/XP scores of -8.290/-8.145 kcal/mol, whereas the tetramethyl ether derivative showed -4.772/-4.511 kcal/mol, with MM-GBSA values of -40.63/-55.42 kcal/mol for leuprolide and favourable binding interactions for the phytochemical. The 100-ns MD simulation demonstrated persistent protein–ligand contacts and maintained secondary structural elements, although substantial RMSD fluctuations indicated considerable conformational flexibility. PASS prediction suggested apoptosis agonist (Pa/Pi = 0.436/0.057), antineoplastic (0.264/0.123), ovulation inhibitor (0.482/0.068), and gonadotropin antagonist (0.445/0.035) activities. Predicted LD50 was 2000 mg/kg (toxicity class 4). A. montanus phytochemicals, particularly the tetramethyl ether derivative, demonstrate promising computational evidence for multitarget modulation of uterine fibroid-associated pathways. Experimental validation is required to establish efficacy, mechanism, and safety.