Identification of α-Mangostin as a Potential Inhibitor of Microtubule Affinity Regulating Kinase 4.
Parvez KhanAarfa QueenTaj Mohammadnull SmitaNashrah Sharif KhanZubair Bin HafeezM D Imtaiyaz HassanSher AliPublished in: Journal of natural products (2019)
Microtubule affinity regulating kinase 4 (MARK4) is a potential drug target for neuronal disorders and several types of cancers. Filtration of naturally occurring compound libraries using high-throughput screening and enzyme assay suggest α-mangostin is a potential inhibitor of MARK4. Structure-based docking and 100 ns molecular dynamics simulation revealed that the binding of α-mangostin stabilizes the MARK4 structure. Enzyme inhibition and binding studies showed that α-mangostin inhibited MARK4 in the submicromolar range with IC50 = 1.47 μM and binding constant (Ka) 5.2 × 107 M-1. Cell-based studies suggested that α-mangostin inhibited the cell viability (MCF-7 and HepG2), induced apoptosis, arrested the cell cycle in the G0/G1 phase, and reduced tau-phosphorylation. This study implicates MARK4 as a new target of α-mangostin, adding an additional lead molecule to the anticancer repertoire.
Keyphrases
- cell cycle
- molecular dynamics simulations
- induced apoptosis
- endoplasmic reticulum stress
- protein kinase
- single cell
- cell proliferation
- human health
- molecular docking
- oxidative stress
- dna binding
- binding protein
- stem cells
- tyrosine kinase
- emergency department
- bone marrow
- risk assessment
- cell therapy
- case control
- mass spectrometry
- mesenchymal stem cells
- dengue virus
- transcription factor
- cerebral ischemia
- aedes aegypti
- subarachnoid hemorrhage