08/24/2026
Computational Drug Discovery Leads to Experimental Validation of a Potential Alzheimer’s Therapeutic Strategy
One of our Reynolds Institute on Aging researchers, Dr. Meenakshisundaram Balasubramaniam recently collaborated with a researcher at Harvard on this discovery. All computational predictions were performed by Dr. Balasubramaniam at UAMS.
Article Title: Zolpidem restores sleep and decreases amyloid in a mouse model Yu L, Yokomizo S, Doan TH, Zhao Q, Ganne A, Balasubramaniam M, Kastanenka KV. Zolpidem restores sleep and decreases amyloid in a mouse model. Alzheimers Dement. 2026 Mar;22(3):e71175. doi: 10.1002/alz.71175. PMID: 41810694; PMCID: PMC12976976.
Link: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71175
A key strength of this study was the integration of advanced computational drug-discovery approaches by Dr. Balasubramaniam with rigorous in vivo experimental validation by Dr. Kastanenka at Harvard Medical School. The computational component employed an unbiased screening strategy to search approximately 2,300 FDA-approved drugs for compounds capable of modulating the GABAA receptor, an important regulator of inhibitory neuronal signaling and sleep. The workflow combined structure-based high-throughput virtual screening, molecular mechanics–based binding free-energy calculations, machine learning and neural-network classification, and molecular dynamics simulations of the intact GABAA receptor embedded within a virtual lipid membrane. This multistep strategy identified zolpidem as a leading candidate and further predicted that its interaction with the receptor could facilitate chloride-ion transport, providing a structural and mechanistic rationale for enhancing GABAergic signaling and restoring sleep-associated neuronal activity.
Importantly, these computational predictions were subsequently validated experimentally in Dr. Kastanenka’s lab at the MassGeneral Institute of Neurodegenerative Diseases and Harvard Medical School using an Alzheimer’s disease mouse model. The experimental studies demonstrated that zolpidem improved NREM sleep stability, restored the sleep-dependent cortical slow oscillations predicted to benefit neuronal function, and, following chronic treatment, significantly reduced cortical amyloid plaque burden and neuronal calcium overload. Zolpidem treatment also improved sleep-dependent contextual memory without adversely affecting locomotor activity. Together, the study demonstrates the power of integrating computational drug repurposing with experimental neuroscience: computational modeling identified and mechanistically prioritized a clinically available compound, while independent in vivo studies provided biological validation that the predicted intervention could improve sleep-associated brain function and reduce key Alzheimer’s disease–related pathologies.
INTRODUCTION Deficits in non–rapid eye movement (NREM) sleep facilitate Alzheimer's disease (AD) progression. Enhancing gamma-aminobutyric acid-ergic (GABAergic) signaling can restore sleep. Unbiase...
