Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)

Abstract

a b s t r a c tRivastigmine 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 p-p interactions and (c) possible CH/p interactions between the benzylic methyl group and the Nmethyl groups of the inhibitor and W82 of the enzyme.

Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks

“…In fact, Compound 1 established hydrogen bonds with residue Ala277 and Asn289 using the hydroxyl groups of the aromatic ring (Figure 3a,b), and productive π-cation interactions between the triphenylphosphonium group and the residue Trp82 were observed. This type of interaction was described to be relevant to the activity [37,38]. Besides, Compound 1 showed strong Coulomb interactions with residues SBG198 (conjugated Ser in the aged enzyme), Asp70 and Glu197.…”

Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

“…Additionally, AntiOxBEN 1 established π-π stacking and π-cation interactions between the triphenylphosphonium group and residues Phe329 and Trp82. The residue Trp82 in the anionic site has been previously described as a key residue that establishes π-cation interactions with choline scaffolds (Nicolet et al, 2003 ; Bacalhau et al, 2016 ). A similar binding mode was detected for AntiOxBEN 2 with three hydroxyl groups in the phenyl ring.…”

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

“…During in silico studies, we evaluated whether carbamate derivative 7 could access the ( h )AChE catalytic triad, specially the Ser203 residue playing a crucial role during carbamoylation. According to the proposed mechanism of rivastagmine carbamoylation [12], the carbamate-to-serine grouping approach starts via a hydrogen bond between the oxygen atom of the carbamate carbonyl group and the hydroxy group of Ser203. Therefore, during the docking study of compound 7 into the ( h )AChE active site (PDB code: 4EY7 [13]), performed using the Gold software (v5.7.2, Cambridge Crystallographic Data Center, CCDC), a hydrogen bond constraint between carbamate carbonyl and hydroxy group of Ser203 was applied.…”

“…Compound 7 docks in the AChE active site with the carbamate group in proximity of Ser203, as imposed by the constraint, but it is positioned much higher in the AChE binding site in two clusters compared to the donepezil and/or the donecopride (Figure 3) [5,6,7,8,9,10,11,12,13]. Consequently, according to our molecular modeling results, compound 7 loses the characteristic interactions of the donecopride ligands family, i.e.,: i) interaction between NH + of piperidine ring through the water molecule lying between the hydroxy groups of two tyrosines (Tyr341 and Tyr337); ii) interaction via C=O group with the backbone NH of Phe295; and iii) the methoxyphenyl moiety is placed a little high but stacking with Trp286 remains possible.…”