Exploring the untapped potential of marine sponge compounds as anticancer agents against ERα of breast cancer

The oceans cover about 96.5 % of all the Earth's water and are virtually unexploited resources for novel drug discovery. Members of almost every phylum are found in the oceans, whereas twelve phyla are exclusively marine. A very limited fraction of marine compounds have been tested in clinically relevant bioassays. Higher resistance of pathogenic microorganisms to antibiotics and disease cells to antitumor medications requires a new phase of novel medicines. The study aims to explore the potential of marine sponges as natural inhibitors for breast cancer therapy using an optimized in-silico technique. We perform in-silico analysis for around two hundred and seventy-two (272) marine sponge compounds against ER alpha of breast cancer using molecular docking and dynamics techniques. The results of the current study were carefully used to screen the compounds with the potential to inhibit ER alpha of breast cancer. For instance, molecular docking analysis reveals that six top-hit selected ligands L1 (Di(IH-indol-3-yl) methanone), L2 (1,2-Bis (1H-indol-3-yl)ethane-1,2-dione), L3 2-(4-benzylpiperidin1-yl)1-(1H-indol-3-yl)ethenone), L4 (5H-Pyrido[4,3-b]carbazole-5,11(6H)-dione), L5 (4H-pyrido[2,3,4-Kl]acridine-4-one), and L6 15-methyl-2, 12,15-triazapentacyclo [11.7.1.03,8,09,21.014,19]henicosa-1,3,5,7,9(21),10,12,14(19),16-nonaene-18,20-dione) show docking scores values ranging from -9.2 kcal/mole to -9.5 kcal/mol in comparison to reference drug inhibitor -8.6 kcal/mole to -9.5 kcal/mol. For comparison purposes, reference drug candidates like tamoxifen, ospemifene, and quinestrol have been studied under the same in-silico methodology. The ligand-protein interactions displayed various types of intermolecular interactions, including hydrogen bond formationand hydrophobic and rc-rc stacking interactions towards the active site of the protein. Explicit molecular dynamic (MD) simulations for 120 ns were executed to mimic the in-vitro aqueous environment and stability pattern of ligand-protein complexes through RMSD, RMSF, Rg, SASA, and intermolecular H-bond. Furthermore, MM/PBSA calculation also confirmed the good binding free energy (Delta Gbind) of L1 (-22.63 kcal/mol), L2 (-13.81 kcal/mol), L3 (-19.23 kcal/mol), L4 (-24.50 kcal/mol), L5 (-14.44 kcal/mol), and L6 (-8.16 kcal/mol) towards ER alpha (1 gwr). Additionally, the ADMET prediction of top-hit ligands was observed to have good drug-likeness criteria (Lipinski RO5) and pharmacokinetic properties. The insilico approach identified ligands L1, L2, L3, L4, L5, and L6 as a promising inhibitor of ER alpha of breast cancer, suggesting in vivo/in vitro studies to investigate their inhibitory potentials further.