期刊
BIOORGANIC CHEMISTRY
卷 111, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.104893
关键词
Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Molecular dynamic simulations; Structure activity relationships; Steroidal alkaloids; Solanocapsine-tacrine hybrids
资金
- Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET)
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT, Argentina)
- Secretaria de Ciencia y Tecnica (SECyT-Universidad Nacional de Cordoba)
- CONICET
- Universidad Nacional de Cordoba
Alzheimer's disease is the most alarming neurodegenerative disorder globally, with cholinesterase inhibitors commonly used in clinical treatments. The strategy of synthesizing hybrid cholinesterase inhibitors has shown improved inhibitory activity and enhanced interactions at multiple sites in the enzyme cavity. This approach should be further explored and exploited in this field.
To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure-activity relationship analysis.
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