Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR).
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.
Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
Patrícia
P
Bacalhau
Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
Amor A
AA
San Juan
Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
Albertino
A
Goth
Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
A Teresa
AT
Caldeira
Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
Rosário
R
Martins
Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal. Electronic address: ajb@uevora.pt.
Anthony J
AJ
Burke
D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000068836:Rivastigmine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase; D000068836:Rivastigmine
Cholinesterase inhibition; Molecular docking; Pseudo-irreversible inhibition; Rivastigmine; STD-NMR