Deep learning-based design and screening of benzimidazole-pyrazine derivatives as adenosine A_2B receptor antagonists

The Adenosine A_2B receptor (A_2BAR) is considered a novel potential target for the immunotherapy of cancer, and A_2BAR antagonists have an inhibitory effect on tumor growth, proliferation, and metastasis. In our previous studies, we identified a class of benzimidazole-pyrazine scaffolds whose derivatives exhibited the antagonistic effect but lacked subtype selectivity towards A_2BAR. In this work, we developed a scaffold-based protocol that incorporates a deep generative model and multilayer virtual screening to design benzimidazole-pyrazine derivatives as potential selective A_2BAR antagonists. By utilizing a generative model with reported A_2BAR antagonists as the training set, we built up a scaffold-focused library of benzimidazole-pyrazine derivatives and processed a virtual screening protocol to discover potential A_2BAR antagonists. Finally, five molecules with different Bemis-Murcko scaffolds were identified and exhibited higher binding free energies than the reference molecule 12o. Further computational analysis revealed that the 3-benzyl derivative ABA-1266 presented high selectivity toward A_2BAR and showed preferred draggability, providing future potent development of selective A_2BAR antagonists.