Alpha-mangostin as an inhibitor of GSK3β in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a breast cancer subtype that does not express the estrogen receptor, the progesterone receptor, or the human epidermal growth factor receptor 2 and that is characterized by high invasiveness, high metastatic potential, and poor prognosis. TNBC lacks receptors and hence cannot be treated by using targeted therapies; as such, the therapeutic potential of Indonesian herbal plants against this disease is worth exploring. Herein, we explore the molecular docking and the molecular dynamics simulations of alpha-mangostin on glycogen synthase kinase 3 beta (GSK3 beta; PDB ID: 4ACC). Our findings reveal that alpha-mangostin has a weaker binding affinity to GSK3 beta than the native ligand (-8.22 kcal/mol), while the latter binds to GSK3 beta with a stronger binding affinity of -8.92 kcal/mol. According to the binding site analysis, the hydrogen bonds of the native ligand on Asp133 and Arg141, while alpha-mangostin only appeared to form a hydrogen bond on the enzyme's Asp133. On the other hand, alpha-mangostin shares similar docking sites with the native ligand (namely, Ile62, Phe67, Val70, and Thr138), thus leading to the conclusion that the native ligand and alpha-mangostin might share a similar molecular mechanism. The molecular dynamics simulation by using the molecular mechanics Poisson-Boltzmann and surface area (MM-PBSA) calculations' method shows that alpha-mangostin maintains a better affinity (with a value of Delta GTotal at -114.463 kJ/mol) as compared with the native ligand (with a respective Delta GTotal value of -75.158 kJ/mop. Our findings are suggestive of alpha-mangostin possessing a valuable potential as an anti-TNBC agent through GSK3 beta inhibition.