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<p>The study aimed to identify the potential acetylcholinesterase (AChE) inhibitors for effective Alzheimer’s treatment from existing FDA-approved drugs through a drug repurposing technique via computational tools. Further, to evaluate the anti-Alzheimer’s potency of the identified drug with the help of a suitable drug delivery system through in vivo pharmacological studies. The molecular docking and dynamics simulation studies indicated that letrozole has a significant binding affinity of -9.6&#xa0;kcal/mol and a better interaction with AChE. The physicochemical properties of letrozole-encapsulated solid lipid nanoparticles (L-SLNs) were characterized and confirmed. Initially, acute toxicity tests of L-SLNs were performed according to OECD 423 guidelines. Biochemical studies revealed that L-SLNs significantly decreased brain Acetylcholine esterase activity induced by scopolamine, but L-SLNs significantly increased AChE activity compared to the Shaam control group. Histopathological evaluation of brain regions revealed significant insights into the neuroprotective potential of L-SLNs in an Alzheimer’s disease (AD) rat model. Treatment with L-SLNs demonstrated dose-dependent neuroprotection across all studied brain regions. At a low dose of L-SLNs (2.5&#xa0;mg/kg), neuronal and glial cells in the cortical and hippocampal regions showed improved regularity, although some disorganization persisted. At a mid-dose of L-SLNs (5&#xa0;mg/kg), the histopathological architecture further normalized, with neurons and glial cells exhibiting regular arrangement and morphology akin to normal cells. The high dose of L-SLNs (10&#xa0;mg/kg) provided the most significant protection, with neuronal and glial cells displaying near-normal arrangement and morphology in the cortical, hippocampal, and Substantia Nigra regions. This study highlights the importance of SLNs-based drug delivery systems in improving the efficacy of existing therapeutic agents in neurodegenerative conditions.</p>

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Computational insights and experimental breakthroughs in identifying next-generation acetylcholinesterase inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月29日

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  • Devaraj Hanumanthappa,
  • Bandral Sunil Kumar,
  • Sandra Ross Olakkengil Shajan,
  • Nandini Markuli Sadashivappa,
  • Shivaraj Kumar Walikar,
  • Basavana Gowda Hosur Dinesh,
  • Srinivas Ganjipete,
  • Selvaraj Kunjiappan,
  • Panneerselvam Theivendren,
  • Kumarappan Chidamabaram,
  • Damodar Nayak Ammunje,
  • Parasuraman Pavadai

摘要

The study aimed to identify the potential acetylcholinesterase (AChE) inhibitors for effective Alzheimer’s treatment from existing FDA-approved drugs through a drug repurposing technique via computational tools. Further, to evaluate the anti-Alzheimer’s potency of the identified drug with the help of a suitable drug delivery system through in vivo pharmacological studies. The molecular docking and dynamics simulation studies indicated that letrozole has a significant binding affinity of -9.6 kcal/mol and a better interaction with AChE. The physicochemical properties of letrozole-encapsulated solid lipid nanoparticles (L-SLNs) were characterized and confirmed. Initially, acute toxicity tests of L-SLNs were performed according to OECD 423 guidelines. Biochemical studies revealed that L-SLNs significantly decreased brain Acetylcholine esterase activity induced by scopolamine, but L-SLNs significantly increased AChE activity compared to the Shaam control group. Histopathological evaluation of brain regions revealed significant insights into the neuroprotective potential of L-SLNs in an Alzheimer’s disease (AD) rat model. Treatment with L-SLNs demonstrated dose-dependent neuroprotection across all studied brain regions. At a low dose of L-SLNs (2.5 mg/kg), neuronal and glial cells in the cortical and hippocampal regions showed improved regularity, although some disorganization persisted. At a mid-dose of L-SLNs (5 mg/kg), the histopathological architecture further normalized, with neurons and glial cells exhibiting regular arrangement and morphology akin to normal cells. The high dose of L-SLNs (10 mg/kg) provided the most significant protection, with neuronal and glial cells displaying near-normal arrangement and morphology in the cortical, hippocampal, and Substantia Nigra regions. This study highlights the importance of SLNs-based drug delivery systems in improving the efficacy of existing therapeutic agents in neurodegenerative conditions.