Mendes Géssica Oliveira, Pita Samuel Silva da Rocha, Carvalho Paulo Batista de, Silva Michel Pires da, Taranto Alex Gutterres, Leite Franco Henrique Andrade
Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Salvador 44036-900, BA, Brazil.
Postgraduate Program in Pharmaceutical Sciences, State University of Feira de Santana, Salvador 44036-900, BA, Brazil.
Pharmaceuticals (Basel). 2023 Jun 15;16(6):880. doi: 10.3390/ph16060880.
Alzheimer's Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or reversing the neurodegenerative process. However, recent studies have shown that inhibiting the enzyme β-secretase 1 (BACE-1) may be able to stop neurodegeneration, making it a promising target. Considering these three enzymatic targets, it becomes feasible to apply computational techniques to guide the identification and planning of molecules capable of binding to all of them. After virtually screening 2119 molecules from a library, 13 hybrids were built and further screened by triple pharmacophoric model, molecular docking, and molecular dynamics (t = 200 ns). The selected hybrid G meets all stereo-electronic requirements to bind to AChE, BChE, and BACE-1 and offers a promising structure for future synthesis, enzymatic testing, and validation.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性记忆丧失和其他受影响的认知功能。AD的药物治疗依赖于乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制剂，仅具有姑息作用，无法阻止或逆转神经退行性过程。然而，最近的研究表明，抑制β-分泌酶1（BACE-1）可能能够阻止神经退行性变，使其成为一个有前景的靶点。考虑到这三个酶靶点，应用计算技术来指导能够与所有这些靶点结合的分子的识别和设计变得可行。从一个文库中虚拟筛选2119个分子后，构建了13个杂合物，并通过三重药效团模型、分子对接和分子动力学（t = 200 ns）进行进一步筛选。所选的杂合物G满足与AChE、BChE和BACE-1结合的所有立体电子要求，并为未来的合成、酶测试和验证提供了一个有前景的结构。
