Dihydroergotamine alleviates circadian rhythm disorders through predicted interaction with to CRY1

Circadian rhythm disorders (CRDs) significantly affect human health, yet therapeutic options remain limited. This study employed a multi-scale virtual screening approach to identify novel drug candidates from FDA-approved small molecules for the treatment of CRDs. We screened 1429 FDA-approved small molecules against five key circadian rhythm-related proteins using molecular docking techniques. The screening process incorporated the TOPSIS algorithm for multi-criteria decision analysis and a machine learning-based assessment of gut microbiota impact. Our computational analysis identified dihydroergotamine (DHE) as the top-ranking candidate, with predicted favorable binding profiles and minimal predicted adverse effects on gut microbiota. Molecular dynamics simulations supported the stability of the modeled DHE-6KX4 complex, indicating sustained interactions in silico over a 100 ns simulation time. Moreover, DHE significantly alleviated physiological and behavioral abnormalities induced by sleep deprivation, including weight loss, recognition memory deficits, and disruption of sleep architecture. Mechanistically, DHE promoted the accumulation of the PER1-CRY1 complex in the nucleus, which subsequently suppressed CLOCK expression, leading to the restoration of normal circadian rhythm function. This integrated computational-experimental approach provides a robust framework for drug repurposing in circadian medicine, establishing DHE as a promising repurposing candidate for CRDs. Notably, the direct interaction between DHE and CRY1 remains a computational prediction that requires further experimental validation.