Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR) |
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| Institution: | 1. Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal;2. Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal;3. Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal;1. Department of Chemistry, University of Life Sciences in Lublin, Akademicka 15, 20-950 Lublin, Poland;2. ?ukasiewicz Research Network – Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland;3. Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;4. Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland;5. Department of Medicinal Chemistry, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;1. Department of Chemistry, State University of Maringá, Maringá, PR, Brazil;2. Department of Technology, State University of Maringá, Umuarama, PR, Brazil;1. Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;2. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States;2. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, United States;3. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States;4. Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, United States;5. BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR 72205, United States;1. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia;2. School of Pharmacy and Applied Science, La Trobe Institute for Molecular Sciences, La Trobe University, Edwards Rd., Bendigo, 3550, Australia |
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| Abstract: | Rivastigmine is a very important drug prescribed for the treatment of Alzheimer’s disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme. |
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| Keywords: | Cholinesterase inhibition Pseudo-irreversible inhibition Rivastigmine Molecular docking STD-NMR |
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