Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Glioblastoma Multiforme (GBM) is the most aggressive adult brain tumor with poor prognosis.
• GBM cells exhibit resistance to conventional therapies due to self-renewal capacity.
• GPR17, an orphan G protein-coupled receptor, is highly expressed in GBM and drives disease progression.

Purpose of the Study:

• To identify high-affinity GPR17 modulators for potential GBM treatment.
• To explore drug repurposing for targeting GPR17 in GBM.
• To validate computational predictions through experimental methods.

Main Methods:

• Virtual screening of 1379 FDA-approved drugs against the GPR17 orthosteric binding pocket.
• Biased-force pulling molecular dynamic (MD) simulations to predict drug-target interactions.
• Experimental validation using GBM cell lines (LN229, SNB19) and cAMP accumulation assays.

Main Results:

• Four FDA-approved drugs (Sacubitril, Victrelis, Pralatrexate, Vorapaxar) were identified as top GPR17 modulator candidates.
• Sacubitril demonstrated full agonist activity, while Vorapaxar showed partial agonist activity for GPR17.
• Sacubitril exhibited potent activity with pEC50 values of 4.841 (LN229) and 4.661 (SNB19).
• siRNA-mediated GPR17 silencing confirmed Sacubitril's targeted binding.

Conclusions:

• Sacubitril and Vorapaxar are identified as promising GPR17-specific drugs for GBM repurposing.
• This study highlights novel therapeutic opportunities for aggressive brain tumors.
• The findings pave the way for developing new treatments for GPR17-related diseases.