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<p>Alzheimer’s disease (AD) is a neurodegenerative disease and principal cause of dementia, affecting more than 55 million people worldwide. The amyloid cascade hypothesis proposes that the β-amyloid peptides, produced by the cleavage of the Amyloid Precursor Protein by BACE-1, are responsible for the onset of the disease. Therefore, BACE-1 has been a target of research and drug design for AD treatment. BACE-1 has a homolog, BACE-2, which is not related to AD and its present and other metabolic pathways. Thus, the design of drugs to treat AD needs to be BACE-1 selective; however, this is not reality for the BACE-1 inhibitors that achieved clinical trials. This work aimed to identify the structural, steric and electronic requirements for the selective inhibition of BACE-1 guided using computational techniques, such as pharmacophore models, molecular docking, molecular dynamic simulations, and free energy calculation. A potential selective BACE-1 inhibitor and selectivity requirements were identified.</p>

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Identification of potential BACE-1 selective inhibitors against Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Alice C. Barros,
  • Mayra R. do Bomfim,
  • Alex G. Taranto,
  • Franco H. A. Leite

摘要

Alzheimer’s disease (AD) is a neurodegenerative disease and principal cause of dementia, affecting more than 55 million people worldwide. The amyloid cascade hypothesis proposes that the β-amyloid peptides, produced by the cleavage of the Amyloid Precursor Protein by BACE-1, are responsible for the onset of the disease. Therefore, BACE-1 has been a target of research and drug design for AD treatment. BACE-1 has a homolog, BACE-2, which is not related to AD and its present and other metabolic pathways. Thus, the design of drugs to treat AD needs to be BACE-1 selective; however, this is not reality for the BACE-1 inhibitors that achieved clinical trials. This work aimed to identify the structural, steric and electronic requirements for the selective inhibition of BACE-1 guided using computational techniques, such as pharmacophore models, molecular docking, molecular dynamic simulations, and free energy calculation. A potential selective BACE-1 inhibitor and selectivity requirements were identified.