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Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase.

ABSTRACT: A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman's assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3?)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low K_i of 0.07 ± 0.01 µM (K_i' = 2.38 ± 0.48 µM) for the inhibition of BChE.

SUBMITTER: Loesche A

PROVIDER: S-EPMC6429507 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase.

Loesche Anne A Kahnt Michael M Serbian Immo I Brandt Wolfgang W Csuk René R

Molecules (Basel, Switzerland) 20190307 5

A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman's assay. We further determined the type of inhi ...[more]

PMID: 30866589

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Project description:AimTo identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function.MethodsLigand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory.ResultsBased on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1.ConclusionThis study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

Project description:Alzheimer's disease is a topic of deep research interest across the global scientific community. Butyrylcholinesterase (BuChE) is an important enzyme, and an interesting anti-Alzheimer's target. Identification or fresh design of promising BuChE-inhibitors is warranted. Virtual screening supported by molecular dynamics simulations has emerged as a key component of present drug-discovery cascades. The research piece aimed at identification of a putative BuChE-inhibitor as a fresh molecular frame that might aid drug design in the context of Alzheimer's disease. The study utilized 'MCULE' to screen a set of 5 million ligands to test their ability to bind to human BuChE. Pharmacokinetic profiling was achieved by the 'SWISS ADME' program. Toxicities were duly assessed. YASARA STRUCTURE version 20.10.4.W.64 was employed to run 133 ns molecular dynamics (MD) simulation for the complex of 'the top screened out inhibitor' and 'the human BuChE enzyme'. The simulation was executed for approx. 4 days (~93 hrs) on an HP ZR30w workstation. YANACONDA, a special language contained in YASARA STRUCTURE was employed to perform complex tasks. Fine resolution figures (notably the RMSD vs time plot) were created. Snapshots were extracted at every 250 ps. The selected ligand, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, exhibited the best overall binding with human BuChE. It interacted with human BuChE through 19 residues. Markedly, 9 of the 19 residues were confirmed to be matching to those of the reference complex (PDB ID 5DYW). Trajectory analysis returned 533 snapshots. The RMSD versus time plot indicated that around 22 ns, equilibrium was achieved and, from then on, the 'BuChE-Top inhibitor' complex remained predominantly stable. From 22 ns and onwards till 133 ns, the backbone RMSD fluctuations were observed to remain limited within a range of 1.2-1.9 Å. The molecule, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, satisfied ADMET requirements. Additionally, the feasibility of the proposed enzyme-inhibitor complex was supported by an adequately extended MD simulation of 133 ns. Hence, the proposed molecule could be a likely lead for designing inhibitor(s) against human BuChE. Scope remains for validatory wet laboratory investigation.

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Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase.

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Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase.

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