Zerumbone binding to estrogen receptors: an in-silico investigation

Breast cancer is the most frequent malignancy among females worldwide. Estrogen receptor (ER) mediate important pathophysiological signaling pathways induced by estrogens, and is regarded as a promising target for the treatment of breast cancer. Zerumbone (2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one; ZER), a chemical constituent present in the Zingiber zerumbet is known to exhibit anti-breast cancer activity by modulating several proteins to induce apoptosis. Medicinal chemists usually exploit lead compounds of natural origin to develop molecules with improved pharmacological properties. Current study is intended to utilize molecular modeling techniques to investigate the interaction of ZER with estrogen receptors. AutoDock was used to predict the binding modes of ZER and target receptors. Stability of the ZER-ER complex was verified by molecular dynamics simulation using Desmond software. Docked ZER was further optimized by density functional theory (DFT) using Gaussian09 program. Analysis of docked conformations in terms of binding energy disclosed estrogen receptor-β (ERβ) as more promising than estrogen receptor-α (ERα). Evaluation of MD trajectories of ZER bound to both ERα and ERβ showed appreciable stability with minimum Cα-atom root mean square deviation shifts. DFT based global reactivity descriptors such as electron affinity, hardness, chemical potential, electronegativity and electrophilicity index, calculated from the energies of highest occupied and lowest unoccupied molecular orbitals underscored the electronic features governing viability of the ZER for interaction with the target receptors. In conclusion, these findings can be exploited to design and develop novel anticancer agents based on the lead compound, ZER.