AI-derived therapeutic development of a serotonin receptor–targeting drug for the treatment of opioid use disorder
Abstract
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. These findings validate GATC’s AI-based platform with its polypharmacy-focused drug development approach and further support the clinical potential of GATC-1021 as a promising therapeutic for those suffering from opioid use disorder.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Valeria Lallai
Department of Neurobiology and Behavior, University of California
Samuel Kho
GATC Health
A. C. Martin
GATC Health
James P. Fowler
Department of Neurobiology and Behavior, University of California
Madison L. Roach
Department of Neurobiology and Behavior, University of California
Kevin Wang
Department of Neurobiology and Behavior, University of California
Kendyl N. Laumann
Department of Neurobiology and Behavior, University of California
Tyler G. Morrison
Department of Psychology, California State University
Mina Palaniappan
Department of Neurobiology and Behavior, University of California
Malia Bautista
Department of Neurobiology and Behavior, University of California
Allison S. Mogul
Department of Neurobiology and Behavior, University of California
Jinjutha E. Cheepluesak
Department of Neurobiology and Behavior, University of California
Bijay Shrestha
GATC Health
Dhanaji M. Lade
GATC Health
Julia E. Lagomarsino
Department of Neurobiology and Behavior, University of California
Vaishnavi Narayan
GATC Health
Jayson Uffens
GATC Health
Waldemar Lernhardt
GATC Health
Saman Mirzaei
GATC Health
Ian Jenkins
GATC Health
Arturo R. Zavala
Department of Psychology, California State University
Jonathan R. T. Lakey
GATC Health
Robert Tinder
GATC Health
Christie D. Fowler
Department of Neurobiology and Behavior, University of California