Artonin E and Structural Analogs from Artocarpus Species Abrogates Estrogen Receptor Signaling in Breast Cancer

Abstract

The increasing rate of mortality ensued from breast cancer has encouraged research into safer and efficient therapy. The human Estrogen receptor α has been implicated in the majority of reported breast cancer cases. Molecular docking employing Glide, Schrodinger suite 2015, was used to study the binding affinities of small molecules from the Artocarpus species after their drug-like properties were ascertained. The structure of the ligand-binding domain of human Estrogen receptor α was retrieved from Protein Data Bank while the structures of compounds were collected from PubChem database. The binding interactions of the studied compounds were reported as well as their glide scores. The best glide scored ligand, was Artonin E with a score of -12.72 Kcal when compared to other studied phytomolecules and it evoked growth inhibition of an estrogen receptor positive breast cancer cells in submicromolar concentration (3.8-6.9 µM) in comparison to a reference standard Tamoxifen (18.9-24.1 µM) within the tested time point (24-72 h). The studied ligands, which had good interactions with the target receptor, were also drug-like when compared with 95% of orally available drugs with the exception of Artoelastin, whose predicted physicochemical properties rendered it less drug-like. The in silico physicochemical properties, docking interactions and growth inhibition of the best glide scorer are indications of the anti-breast cancer relevance of the studied molecules.

Keywords: Artocarpus; Artonin E; human estrogen receptor; in silico; molecular docking.

Figure 1

X-ray Structure of PDB ID 2IOG: (a) Target receptor, 2IOG with co-crystallized native ligand shown in purple sticks and amino acid residues shown as green sticks with their three-letter code and name; and (b) redooked native ligand superimposed with the crystallized native ligand within the binding pocket of 2IOG showing hydrogen bonding in white surface cartoon.

Figure 2

Docking control. Top ranked ligand pose for the native ligand, compound 11F 3-(4-hydroxyphenyl)-1-methylpropyl]-2-[2-phenyl-6-(2-piperidin-1-ylethoxy)-1h-indol-3-yl]acetamide-LBD hERα superimposed with co-crystallized native ligand.

Figure 3

Molecular interactions of studied ligands with crucial amino acids at the ligand-binding domain of hERα: (a) Artonin E; (b) Artobiloxanthone; (c) Artelastin; (d) Artonin U; (e) Cycloartocarpesin; (f) Artonin L; (g) Artonin Y; (h) Artonin T; (i) Artonin S; (j) Native ligand, 11F; (k) Tamoxifen; and (l) A flavone skeleton.

Figure 3

Molecular interactions of studied ligands with crucial amino acids at the ligand-binding domain of hERα: (a) Artonin E; (b) Artobiloxanthone; (c) Artelastin; (d) Artonin U; (e) Cycloartocarpesin; (f) Artonin L; (g) Artonin Y; (h) Artonin T; (i) Artonin S; (j) Native ligand, 11F; (k) Tamoxifen; and (l) A flavone skeleton.

Figure 4

Dose–response curves of time-interval effect for: (a) Artonin E and (b)Tamoxifen on MCF 7.