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...
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Wiley
2025-08-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70443 |
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| author | Martin Nwadiugwu Md Selim Reza Boluwatife Afolabi Demetrius M. Maraganore Hui Shen Hongwen Deng |
| author_facet | Martin Nwadiugwu Md Selim Reza Boluwatife Afolabi Demetrius M. Maraganore Hui Shen Hongwen Deng |
| author_sort | Martin Nwadiugwu |
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| description | 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 Å2). 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-de00cda9160d43b4acfc90d2d085e3cc2025-08-25T18:28:44ZengWileyClinical and Translational Medicine2001-13262025-08-01158n/an/a10.1002/ctm2.70443Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's diseaseMartin Nwadiugwu0Md Selim Reza1Boluwatife Afolabi2Demetrius M. Maraganore3Hui Shen4Hongwen Deng5Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine Tulane University School of Medicine, Tulane University New Orleans Louisiana USATulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine Tulane University School of Medicine, Tulane University New Orleans Louisiana USATulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine Tulane University School of Medicine, Tulane University New Orleans Louisiana USADepartment of Neurology, Center for Clinical Neurosciences Tulane University School of Medicine, Tulane University New Orleans Louisiana USATulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine Tulane University School of Medicine, Tulane University New Orleans Louisiana USATulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine Tulane University School of Medicine, Tulane University New Orleans Louisiana USAAbstract 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 Å2). 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.https://doi.org/10.1002/ctm2.70443Alzheimer's diseasedrug repurposinggene regulatorsLasmiditansnRNA‐Seq |
| spellingShingle | Martin Nwadiugwu Md Selim Reza Boluwatife Afolabi Demetrius M. Maraganore Hui Shen Hongwen Deng Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease Clinical and Translational Medicine Alzheimer's disease drug repurposing gene regulators Lasmiditan snRNA‐Seq |
| title | Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease |
| title_full | Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease |
| title_fullStr | Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease |
| title_full_unstemmed | Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease |
| title_short | Integrative snRNA‐seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease |
| title_sort | integrative snrna seq molecular docking and dynamics simulations identifies lasmiditan as drug candidate for alzheimer s disease |
| topic | Alzheimer's disease drug repurposing gene regulators Lasmiditan snRNA‐Seq |
| url | https://doi.org/10.1002/ctm2.70443 |
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