Molecular docking appraisal of Dysphania ambrosioides phytochemicals as potential inhibitor of a key triple-negative breast cancer driver gene.

Triple-negative breast cancer (TNBC) is a lethal and aggressive breast cancer subtype. It is characterized by the deficient expression of the three main receptors implicated in breast cancers, making it unresponsive to hormone therapy. Hence, an existing need to develop a targeted molecular therapy for TNBC. The PI3K/AKT/mTOR signaling pathway mediates critical cellular processes, including cell proliferation, survival, and angiogenesis. It is activated in approximately 10-21% of TNBCs, emphasizing the importance of this intracellular target in TNBC treatment. AKT is a prominent driver of the PI3K/AKT/mTOR pathway, validating it as a promising therapeutic target. Dysphania ambrosioides is an important ingredient of Nigeria's traditional herbal recipe for cancer treatment. Thus, our present study explores its anticancer properties through a structure-based virtual screening of 25 biologically active compounds domiciled in the plant. Interestingly, our molecular docking study identified several potent inhibitors of AKT 1 and 2 isoforms from D. ambrosioides. However, cynaroside and epicatechin gallate having a binding energy of - 9.9 and - 10.2 kcal/mol for AKT 1 and 2, respectively, demonstrate considerable drug-likeness than the reference drug (capivasertib), whose respective binding strengths for AKT 1 and 2 are - 9.5 and - 8.4 kcal/mol. Lastly, the molecular dynamics simulation experiment showed that the simulated complex systems of the best hits exhibit structural stability throughout the 50 ns run. Together, our computational modeling analysis suggests that these compounds could emerge as efficacious drug candidates in the treatment of TNBC. Nevertheless, further experimental, translational, and clinical research is required to establish an empirical clinical application.

Graphical abstract: A structure-based virtual screening and simulation of Dysphania ambrosioides phytochemicals in the active pocket of AKT 1 and 2 isoforms.