Integrating Deep Learning and Molecular Dynamics to Identify GPR17 Ligands for Glioblastoma Therapy

Guanine Protein-coupled Receptor 17 (GPR17) plays pivotal roles in various
physiological processes and diseases. However, the discovery of ligands binding to GPR17 remains
an active area of research. Methods: In this study, we utilized our recently published GPCR-specific deep learning approach,
molecular docking, and molecular dynamics simulations. Specifically, the Deep GPCR model, employing
graph convolutional networks, was used to screen the extensive ZINC database for potential ligands.
Results: This computational pipeline identified three highly promising lead compounds,
ZINC000044404209, ZINC000229938097, and ZINC000005158963. Molecular dynamics simulations
confirmed the stability of the protein-ligand complexes, while binding free energy calculations
highlighted the crucial molecular forces stabilizing these interactions. Notably,
ZINC000229938097 exhibited particularly favorable binding energy values among the compounds
assessed. Conclusion: Our study underscores the efficacy of computational methodologies in identifying potential
drug candidates targeting GPR17. Understanding the molecular mechanisms underlying
GPR17 activation holds significant promise for developing tailored therapies for Glioblastoma Multiforme.