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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and impaired cholinergic signaling. Natural polyphenolic compounds have gained attention for their antioxidant, anti-inflammatory, and multi-target neuroprotective effects. In this study, we explored the potential of gentisic acid and alpha-resorcylic acid as therapeutic candidates against AD using a combination of computational and experimental approaches. We first identified potential protein targets for these compounds using SwissTargetPrediction and STITCH databases and compiled 67 AD-related genes from GeneCards. Network analysis highlighted acetylcholinesterase (AChE) as a key target, supported by its established role in AD pathology. Molecular docking showed that gentisic acid and alpha-resorcylic acid bind effectively to AChE, with docking scores of − 6.6 and − 6.9&#xa0;kcal/mol, respectively, compared to standard drugs donepezil (− 9.2&#xa0;kcal/mol) and galantamine (− 7.7&#xa0;kcal/mol). Molecular dynamics simulations over 100 ns confirmed the stability of these ligand–protein complexes, with RMSD values remaining below 3 Å and consistent hydrogen-bond interactions throughout the simulation. Experimental validation revealed that both compounds inhibit AChE in a concentration-dependent manner, with IC₅₀ values of 3.59&#xa0;µg/mL for gentisic acid and 89.99&#xa0;µg/mL for alpha-resorcylic acid. Functional enrichment analyses further indicated that these compounds may influence multiple pathways relevant to AD, including Tau phosphorylation, neuropeptide receptor activity, glycerolipid metabolism, and anti-inflammatory signaling. Together, these findings suggest that gentisic acid and alpha-resorcylic acid can act as multi-target agents with promising neuroprotective effects. Their moderate binding to AChE, coupled with favorable pharmacological properties, positions them as potential leads for the development of novel therapies for AD. These results provide a strong foundation for future preclinical and clinical investigations into their therapeutic applications.</p>

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Therapeutic Potential of Phytocompounds Gentisic Acid and Alpha Resorcylic Acid against Alzheimer’s Disease: A Network Pharmacology, In Silico, and In Vitro Approach

  • 期刊论文

  • 发表日期：

    2025年11月10日

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  • Urvashi Soni,
  • Rohini Pujari

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and impaired cholinergic signaling. Natural polyphenolic compounds have gained attention for their antioxidant, anti-inflammatory, and multi-target neuroprotective effects. In this study, we explored the potential of gentisic acid and alpha-resorcylic acid as therapeutic candidates against AD using a combination of computational and experimental approaches. We first identified potential protein targets for these compounds using SwissTargetPrediction and STITCH databases and compiled 67 AD-related genes from GeneCards. Network analysis highlighted acetylcholinesterase (AChE) as a key target, supported by its established role in AD pathology. Molecular docking showed that gentisic acid and alpha-resorcylic acid bind effectively to AChE, with docking scores of − 6.6 and − 6.9 kcal/mol, respectively, compared to standard drugs donepezil (− 9.2 kcal/mol) and galantamine (− 7.7 kcal/mol). Molecular dynamics simulations over 100 ns confirmed the stability of these ligand–protein complexes, with RMSD values remaining below 3 Å and consistent hydrogen-bond interactions throughout the simulation. Experimental validation revealed that both compounds inhibit AChE in a concentration-dependent manner, with IC₅₀ values of 3.59 µg/mL for gentisic acid and 89.99 µg/mL for alpha-resorcylic acid. Functional enrichment analyses further indicated that these compounds may influence multiple pathways relevant to AD, including Tau phosphorylation, neuropeptide receptor activity, glycerolipid metabolism, and anti-inflammatory signaling. Together, these findings suggest that gentisic acid and alpha-resorcylic acid can act as multi-target agents with promising neuroprotective effects. Their moderate binding to AChE, coupled with favorable pharmacological properties, positions them as potential leads for the development of novel therapies for AD. These results provide a strong foundation for future preclinical and clinical investigations into their therapeutic applications.