Abstract
The discovery of a potential ligand-targeting G protein-coupled receptor 17 (GPR17) is important for developing chemotherapeutic agents against glioblastoma multiforme (GBM). We used the integration of ligand- and structure-based cheminformatics and experimental approaches for identifying the potential GPR17 ligand for GBM treatment. Here, we identified a novel indoline-derived phenolic Mannich base as an activator of GPR17 using molecular docking of over 6000 indoline derivatives. One of the top 10 hit molecules, CHBC, with a glide score of −8.390 was synthesized through a multicomponent Petasis borono–Mannich reaction. The CHBC–GPR17 interaction leads to a rapid decrease of cAMP and Ca2+. CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC50 of 85 μM, whereas the known agonist MDL29,951 showed a negligible effect. Our findings suggest that the phenolic Mannich base could be a better GPR17 agonist than MDL29,951, and further uncovering their pharmacological properties could potentiate an inventive GBM treatment.
Highlights
In the effort to facilitate the development of more effective target therapies, G protein-coupled receptor (GPCR) has been revealed as a promising candidate that plays a prominent role in the cell signaling process
G protein-coupled receptor 17 (GPR17) is an orphan GPCR physiologically located between uracil nucleotides and cysteinyl leukotrienes (CysLTs) that transmits signals through the Gαi protein, leading to adenylyl cyclase inhibition.[5,6]
The target protein GPR17 is bound to a known GPR17 activator, and the interactions formed have been taken as ref 2
Summary
Human glioblastoma multiforme (GBM), a stage IV glioma, is one of the most common intrinsic and aggressive brain tumors in adults with a median survival of 14.6 months.[1,2] GBM is among the most difficult tumors to treat since they tend to recur and resist to the current therapy approach despite the combination treatment of surgery, radiation, and chemotherapy with DNA alkylating agents, such as temozolomide (TMZ).[1,3] In the effort to facilitate the development of more effective target therapies, G protein-coupled receptor (GPCR) has been revealed as a promising candidate that plays a prominent role in the cell signaling process. Having in mind the reported importance of indole substituents in surrendering agonist activity to the heterocyclic core, non-commercial substituted indolines were considered for the elaboration of a second set of ligands (Figure 2b).[22] Initially, 3234 ligand entries were modeled and docked with GPR17 target through the virtual screening workflow using glide.[3] The glide score (gscore) value was used as the criterion to choose the bestdocked compounds among the studied compounds from the dataset. At a 100 μM treatment concentration, nearly 37 and 50% growth inhibition were recorded in SNB19 and LN229, respectively, whereas less than 5% growth inhibition was observed in MEF at 100 μM This result suggests that the GPR17 agonist can induce specific cytotoxicity effect on GBM cells. For SNB19 treated with CHBC and TMZ, the IC50 values were 85.54 ± 5.20 and 69.87 ± 4.64 μM, respectively
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
