Tailored Modeling of Rivastigmine Derivatives as Dual Acetylcholinesterase and Butyrylcholinesterase Inhibitors for Alzheimer's Disease Treatment |
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Authors: | Fatima Y Adeowo Tosin P Oyetunji Murtala A Ejalonibu Umar Ndagi Hezekiel M Kumalo Monsurat M Lawal |
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Institution: | 1. Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, 4001 South Africa;2. Faculty of Public Health, University of Ibadan, Nigeria;3. Center for Trans-Sahara Disease, Vaccine and Drug Research, IBB University Lapai, Niger State, Minna, Nigeria |
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Abstract: | Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood-brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of −41.1/−39.5 kcal mol−1 while rivastigmine binds with −32.7/−30.7 kcal mol−1 for these enzymes. The study revealed RL2 (4-fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management. |
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Keywords: | Alzheimer's disease (AD) Acetylcholinesterase (AChE) butyrylcholinesterase (BuChE) dual inhibitors blood-brain barrier (BBB) score activation and binding energy |
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