Exploring some marine-derived manzamine compounds for uterine fibroid treatment: molecular docking and dynamics studies
摘要
Women commonly experience uterine fibroids, which are benign tumors within the uterine muscle characterized by irregular extracellular matrix deposition and abnormal smooth muscle cell proliferation, often with a tendency to recur. In this study, we explored the therapeutic promise of various marine-derived Manzamine compounds (1-25), some of which exhibit significant anti-tumor properties, for treating uterine fibroids. Our computational results align closely with recent experimental evidence indicating that Manzamine A inhibits uterine fibroid cell proliferation through selective targeting of human sterol O-acyltransferases, thereby reducing cholesterol esterification. To evaluate their inhibitory potential, ligands 1-25 was subjected to docking, molecular mechanics-generalized Born surface area (MM-GBSA), molecular dynamics (MD) and well-tempered metadynamics (WT-MetaD) simulations against sterol O-acyltransferase 1 (SOAT1) as the identified target. Compound 10 shows the highest G-score (-13.96) among all compounds, while others such as 11, 18, 16, 2, 24, 6, and 19 show greater activity against SOAT1 compared to Manzamine A. Ligand binding is significantly influenced by the residues GLU461, TRP420, TYR417, PHE476, PHE479, LEU377, ILE376, VAL374, and PHE378 in the SOAT1 protein structure. MD simulations explored dynamic interactions in the 10/SOAT1 complex, while WT-MetaD confirmed the docking study results and identified energetically favored conformations of protein-ligand complex. Ligands 10, 11, 18, 16, 2, 24, 6, and 19, with their high Glide scores and unique functional groups, are expected to exhibit notable SOAT1 activity and thus merit further investigation.
Graphical Abstract