Integrative snRNA-seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease.

BACKGROUND

Alzheimer's disease (AD) is a growing healthcare crisis with limited effective therapies. This study aims to identify new candidate drugs that can be repurposed using key transcriptional regulators (DERs) in AD as therapeutic targets.

METHODS

Multi-cohort single-nucleus RNA sequencing (snRNA-seq) data from the prefrontal cortex were analysed to identify DERs. Molecular docking and dynamic simulations analysis evaluated interactions between DERs and 2200 Food and Drug Administration-approved drugs to assess binding stability, whilst pharmacokinetic parameters relevant to blood-brain barrier permeability were evaluated.

RESULTS

We identified 20 key DERs associated with AD. Lasmiditan stood out as the most promising drug amongst other drug candidates (Vorapaxar, Bictegravir, Tonaftate, Fluspirilene, Lisuride, Olaparib) interacting with five DERs: ZEB2, APP, PAX6, ETV6, and ST18. Lasmiditan-ETV6 complex showed the best binding stability (RMSD: 2.98 Å, H-bonds: 68.38) and optimal passive diffusion (LogP3-4, TPSA 60-75 Å).

DISCUSSION

Lasmiditan is a potential AD therapeutic candidate that warrants further preclinical validation.

KEY POINTS

20 key transcriptional regulators (DERs) were identified linked to AD in myeloid, and neuronal cell populations. The DERs correlated with Braak stage, APOE genotype, and aging. ETV6 is a potentially viable therapeutic target due to its ability to form stable and strongly interacting complexes across multiple drugs. Lasmiditan showed the strongest binding to ETV6 (RMSD: 2.98 Å, H-bonds: 68.38) and optimal blood-brain-barrier (BBB) penetration (LogP 3-4, TPSA 60-75). Lasmiditan is a potentially promising AD therapeutic candidate that warrants further preclinical validation.