In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier

Abstract

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman’s spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood–brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer’s disease.

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

“…Particularly, compound 1 (Figure 2) had the highest affinity and also formed identical interactions with the amino acids of the catalytic site of AChE similar to the observed for donepezil, especially with residues Trp86 and Tyr337 [20]. An identical strategy was performed to study other natural products, namely canadine derivatives [21], cinnamic acid derivatives, indolinones and cycloartane triterpenoids [22], phenolic acid derivatives [23], and synthetic compounds, such as arylisoxazole-phenylpiperazine derivatives [24], dipropargyl substituted diphenylpyrimidines [25], quinoline chalcone derivatives [26], and N-(4-methylpyridin-2-yl)thiophene-2-carboxamide analogs [27], as displayed in (Figure 2). Ranjan's research group [28] studied the affinity of several organophosphate derivatives against AChE (PDB#1B41) using docking-based virtual screening combined with molecular dynamics simulations.…”

Design and Synthesis of Novel Arylisoxazole‐Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease

“…The corresponding protein crystal structures for AChE (1EVE) and BChE (1P0P) were retrieved from the protein data bank and co-crystal ligand donepezil was re-docked using smina in Linux platform. [25] The range of minimized affinity values of the poses of ligands 11h, 11j and 11e were À 12.82 to À 11.73, À 12.50 to À 11.10 and À 11.1 to À 10.4 kcal/ mol, respectively.…”

“…Neuroprotective effect of compound 11h against damage induced by Aβ [25][26][27][28][29][30][31][32][33][34][35] was investigated in PC12 cells by MTT assay. [24] This compound showed 6.4 % protection at the concentration of 25 μM comparing with rutin with 13.4 % protection at the same concentration.…”

“…The neuroprotective effect of compound 11h in protecting neuronal PC12 cells against damage induced by Aβ [25][26][27][28][29][30][31][32][33][34][35] was examined according to our previous report. [24] Molecular Docking Study A docking study was performed using Auto Dock Tools (version 1.5.6) and the pdb structures of 1EVE (AChE) and 1P0I (BChE) were taken from the Brookhaven protein database (http://www.rcsb.org).…”

Recent progress in translational engineeredin vitromodels of the central nervous system

“…integrating machine learning and deep learning methods; see Yuan et al , 2018 ), and can be used to supplement or even replace some experimental procedures. Computer-based models offer the possibility to synthetize, prescreen and virtually test novel drugs, limiting the need for intensive laboratory experiments and expensive clinical trials, and accelerating the drug development process ( Naik and Cucullo, 2012 ; Alsarrani and Kaplita, 2019 ; Chlebek et al ., 2019 ). Nevertheless, non-cell-based models are not yet sufficient on their own, and the results obtained with such studies must be validated by (cell-based) in vitro and in vivo studies (e.g.…”