First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease
| العنوان: | First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease |
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| المؤلفون: | Leonardo Pisani, Rosa Purgatorio, Cosimo Altomare, Marco Catto, Mariagrazia Rullo, Orazio Nicolotti, Nicola Gambacorta, Modesto de Candia |
| المصدر: | Molecules Volume 26 Issue 17 Molecules, Vol 26, Iss 5208, p 5208 (2021) |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Aché, Pharmaceutical Science, Organic chemistry, Pharmacology, isonipecotamides, Article, Analytical Chemistry, Structure-Activity Relationship, chemistry.chemical_compound, Thrombin, QD241-441, Piperidines, Alzheimer Disease, Drug Discovery, medicine, Animals, Humans, Potency, Physical and Theoretical Chemistry, Receptor, Butyrylcholinesterase, Cholinesterase, chemistry.chemical_classification, biology, acetylcholinesterase, Acetylcholinesterase, antithrombotic agents, language.human_language, Molecular Docking Simulation, Enzyme, chemistry, Chemistry (miscellaneous), Factor Xa, butyrylcholinesterase, language, biology.protein, Molecular Medicine, Cattle, Cholinesterase Inhibitors, Alzheimer’s disease, Factor Xa Inhibitors, medicine.drug |
| الوصف: | Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1420-3049 |
| DOI: | 10.3390/molecules26175208 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bc804f4d39259642caf612fccf11ceb |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8bc804f4d39259642caf612fccf11ceb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14203049 |
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| DOI: | 10.3390/molecules26175208 |