Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Authors

Ayesha Naseer, Naveed Iqbal, Ishrat Bibi, Syed Ali Raza Shah, Misbah Khalid, Ayesha Khalid

Published in

In silico pharmacology. Volume 14. Issue 3. Pages 259. Epub Oct 17, 2026.

Abstract

Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have converging molecular pathologies such as neuroinflammation, mitochondrial dysfunction, and axonal degeneration, but do not have broadly effective disease-modifying therapies. A novel computational strategy was used in this study with an integrated in-silico pipeline to determine common candidate hub genes across AD, PD, and ALS and to computationally screen candidate inhibitors. The gene expression datasets were retrieved from the Gene Expression Omnibus database and analyzed with limma R package for blood-derived gene expression datasets for AD (GSE63060), PD (GSE99039) and ALS (GSE112680). A multi-dataset intersection analysis revealed 138 genes commonly upregulated and 0 commonly downregulated genes, which were functionally enriched in immune regulation, apoptotic signaling and mitochondrial instability pathways. Protein-protein interaction network analysis identified three key genes (MMP9, PTPN6 and TNFRSF1A) as high-confidence candidate hub genes for AD, PD, and ALS. The ZINC library of 34,853 compounds was screened for drug-like properties using QikProp to yield 16,466 drug-like compounds. Based on the comparative screening results, the structure of MMP9 (PDB ID: 8K5Y) was chosen for further analysis and two of the selected compounds ZINC04582833, ZINC00047690 were identified as the two highest ranked compounds with docking scores of - 10.4 and - 9.7 kcal/mol respectively. Both complexes were further evaluated by 100 ns MD simulations, showing RMSD profile stability, maintained secondary structure for both complexes. The results in this study make ZINC04582833 and ZINC00047690 computationally prioritized candidates for shared neurodegenerative targets for experimental validation.
The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00774-6.

PMID:
42894599
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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