Inhibition Of Human Butyrylcholinesterase Research Articles

Kinetics of human butyrylcholinesterase inhibition by 1,9-dimethyl-methylene blue

Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder, characterized by β-amyloid plaques, neurofibrillary tangles and loss of cholinergic neurons. Butyrylcholinesterase (BChE) inhibition is one of the most critical strategy for the treatment of AD since BChE causes inactivation of neurotransmitter acetylcholine and has positive effects on promoting the formation of β-amyloid fibrils. Our previous studies showed that various phenothiazine-derived compounds such as thionine and toluidine blue O (TBO) cause a potent inhibition of human cholinesterases. TBO was also found to reduce amyloid precursor protein processing in-vitro and in-vivo models of AD. In this study, it was aimed to determine the inhibitory effect of 1,9-dimethyl-methylene blue (DMMB), a phenothiazine-derived compound, on human plasma BChE and explore its inhibitory mechanism. The inhibition of human BChE was assessed by the colorimetric method of Ellman using butyrylthiocholine as substrate and 0-0.375 μM of DMMB. The kinetic findings showed that DMMB acts as a linear mixed-type inhibitor of human BChE with Ki value of 23 ± 0.004 nM and α= 3.6 ± 1.6. It was concluded that DMMB, which is a potent inhibitor effective at nM level may be helpful in designing new cholinesterase inhibitors for the treatment of AD.

LiSiCA: A Software for Ligand-Based Virtual Screening and Its Application for the Discovery of Butyrylcholinesterase Inhibitors

We developed LiSiCA (ligand similarity using clique algorithm)--ligand-based virtual screening software that uses a fast maximum clique algorithm to find two- and three-dimensional similarities between pairs of molecules and applied it to the discovery of novel potent butyrylcholinesterase inhibitors. LiSiCA, which runs in parallel on multiple processor cores, was successfully tested on the Database of Useful Decoys-Enhanced, to evaluate its ability to discriminate active molecules from decoys. We then applied LiSiCA for the discovery of novel inhibitors of human butyrylcholinesterase, a promising anti-Alzheimer target, using a known inhibitor as the reference compound. We demonstrated that LiSiCA is capable of finding potent nanomolar inhibitors, whose scaffolds differed from the reference compound, thus proving its ability for scaffold hopping and usefulness in drug discovery.

Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase

Selected flavonoids: galangin, kaempferol, quercetin, myricetin, fisetin, apigenin, luteolin and rutin, reversibly inhibited human butyrylcholinesterase (BChE, EC 3.1.1.8). Inhibition potency of the flavonoids we attributed to their chemical structure, i.e., the number of OH groups and their side on the phenyl ring. The most potent BChE inhibitor among the tested flavonoids was galangin, which showed 12 times higher preference for binding to BChE (7 μmol/L) than to the related enzyme human acetylcholinesterase (AChE, EC 3.1.1.7). Docking study showed that flavonoids bind to the BChE active site by forming multiple hydrogen bonds and π-π interactions. The UV-VIS (200–500 nm) absorption spectra of the flavonoid phosphate buffer solution (pH 7.4), with the exception of rutin, revealed time dependant changes indicating precipitation of flavonoids or in the case of myricetin, a change in the chemical structure resulting in a BChE non-inhibiting specie. Selected flavonoids showed no cytotoxic effect on HepG2 and A549 cell lines at concentrations up to 200 μmol/L. Cytotoxicity was observed only for fisetin, apigenin and luteolin in the THP-1 cell line with IC 50 of 30, 60 and 70 μmol/L, respectively.

Chemical and Biochemical Studies on the Conversion of Alkylating Agents to Phosphorothiolates and their Subsequent Sequestration by Cholinesterases

Abstract In endeavor to develop a universal, mild decontamination solution of vesicants and nerve agents, we have examined the possibility of transforming bis(β-chloroethyl)sulfide (sulfur mustard; HD) to an organophosphorus (OP) compound that will have a significant preference for inhibition of human butyrylcholinesterase (HuBChE) compared with acetylcholinesterase (AChE).