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

Abstract

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 α-mangostin on glycogen synthase kinase 3β (GSK3β; PDB ID: 4ACC). Our findings reveal that α-mangostin has a weaker binding affinity to GSK3β than the native ligand (−8.22 kcal/mol), while the latter binds to GSK3β 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 α-mangostin only appeared to form a hydrogen bond on the enzyme’s Asp133. On the other hand, α-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 α-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 α-mangostin maintains a better affinity (with a value of ΔGTotal at −114.463 kJ/mol) as compared with the native ligand (with a respective ΔGTotal value of −75.158 kJ/mol). Our findings are suggestive of α-mangostin possessing a valuable potential as an anti-TNBC agent through GSK3β inhibition.

Communicated by Ramaswamy H. Sarma

Keywords:

• Triple-negative breast cancer
• α-mangostin
• GSK3β
• molecular docking
• molecular dynamics

Disclosure statement

No potential conflict of interest reported by the authors.

Additional information

Funding

The Authors gratefully acknowledge Kementerian Pendidikan dan Kebudayaan, Indonesia for Kemenristek BRIN grant with contract no 1207/UN6.3.1/PT.00/2021 and Universitas Padjadjaran, Indonesia for Academic Leadership Grant with contract no 1959/UN6.3.1/PT.00/2021.