Atranorin (ATR), lichenized secondary metabolite and depside molecule with several biological potentials such as antimicrobial, anticancer, anti-inflammatory, antinociceptive, wound healing and photoprotective activities. Cytotoxic reports of ATR are documented in several cancer cells and in vivo models but its molecular interaction studies are poorly understood. Therefore, in this present investigation, we have used the in silico studies with biological validation of the molecular targets for the anti-breast cancer mechanism of ATR. The molecular docking studies with the breast cancer oncoproteins such as Bcl-2, Bax, Akt, Bcl-w and Bcl-xL revealed the highest interaction was observed with the Akt followed by Bax, Bcl-xL and Bcl-2 & least with the Bcl-w proteins. The cytotoxicity studies showed ATR selectively inhibited MDA MB-231 and MCF-7 breast cancer cells in differential and dose-dependent manner with the IC50 concentration of 5.36 ± 0.85 μM and 7.55 ± 1.2 μM respectively. Further mechanistic investigations revealed that ATR significantly inhibited ROS production and significantly down-regulated the anti apoptotic Akt than Bcl-2, Bcl-xL and Bcl-w proteins with a significant increase in the Bax level and caspases-3 activity in the breast cancer cells when comparison with Akt inhibitor, ipatasertib. In vitro biological activities well correlated with the molecular interaction data suggesting that atranorin had higher interaction with Akt than Bax and Bcl-2 but weak interaction with Bcl-w and Bcl-xL. In this present study, the first time we report the interactions of atranorin with molecular targets for anti-breast cancer potential. Hence, ATR represents the nature-inspired molecule for pharmacophore moiety for design in targeted therapy.Communicated by Ramaswamy H. Sarma.
Keywords: Breast cancer; atranorin; biological validation; cytotoxicity; interaction.