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

Abstract

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 Ų).

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

Keywords

Alzheimer's disease / drug repurposing / gene regulators / Lasmiditan / snRNA-Seq

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