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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,14]]},"abstract":"<jats:p>The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, including fentanyl. Here, we developed a therapeutic drug based on an AI-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. Two top candidate compounds, GATC-021 and GATC-1021, were synthesized and validated with in vitro screening for target specificity. Thereafter, the drug candidates were examined for their effectiveness in modulating opioid reinforcement and intake. GATC-1021 emerged as the most efficacious compound as it significantly decreased fentanyl intake in both male and female rats, without any notable side effects. GATC-1021 was further found to modulate gene expression patterns in addiction-relevant brain regions following fentanyl-induced alterations. 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