Precision Targeting in Gastric Cancer: AI-Driven Discovery of MET,ADORA2A,CDK5R1,and ADORA1

Abstract

In this study, we integrated computational and experimental approaches to identify novel therapeutic targets and candidate compounds for gastric cancer (GC). Through in silico analyses, including target prediction, pathway enrichment, and molecular docking, four key proteins—MET, ADORA2A, CDK5R1, and ADORA1—were identified as critical regulators of tumor proliferation, metastasis, and drug resistance pathways (e.g., Semaphorin interactions and NTRK1 signaling). Molecular docking and dynamics simulations revealed strong binding affinities and structural stability between selected compounds and these targets, prioritizing ADORA1 as a promising therapeutic node. To validate these findings, we synthesized compound 3 via a two-step chemical route, yielding a white solid product with 63% overall efficiency. Structural characterization by High-Resolution Mass Spectrometry (HRMS) and ¹H Nuclear Magnetic Resonance (NMR) confirmed its identity. In vitro inhibition assays demonstrated that compound 3 exhibited potent activity against ADORA1, with a mean Half-Maximal Inhibitory Concentration (IC₅₀) of 0.23 nM—approximately twofold more effective than the positive control antagonist Dipropylcyclopentylxanthine (DPCPX) (IC₅₀ = 0.46 nM). These results highlight compound 3 as a promising lead compound for further development in GC therapy, with potential to modulate ADORA1-mediated signaling pathways.