Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions.

The Biochemical Journal
D BarakA Shafferman

Abstract

The role of the functional architecture of the HuAChE (human acetylcholinesterase) in reactivity toward the carbamates pyridostigmine, rivastigmine and several analogues of physostigmine, that are currently used or considered for use as drugs for Alzheimer's disease, was analysed using over 20 mutants of residues that constitute the interaction subsites in the active centre. Both steps of the HuAChE carbamylation reaction, formation of the Michaelis complex as well as the nucleophilic process, are sensitive to accommodation of the ligand by the enzyme. For certain carbamate/HuAChE combinations, the mode of inhibition shifted from a covalent to a noncovalent type, according to the balance between dissociation and covalent reaction rates. Whereas the charged moieties of pyridostigmine and rivastigmine contribute significantly to the stability of the corresponding HuAChE complexes, no such effect was observed for physostigmine and its analogues, phenserine and cymserine. Moreover, physostigmine-like ligands carrying oxygen instead of nitrogen at position -1 of the tricyclic moiety (physovenine and tetrahydrofurobenzofuran analogues) displayed comparable structure-function characteristics toward the various HuAChE enzymes. The esse...Continue Reading

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Citations

Dec 12, 2012·Journal of Molecular Modeling·Chandran RemyaChittalakkottu Sadasivan
Apr 6, 2012·Archives of Pharmacal Research·Qun-you TanJing-qing Zhang
May 6, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Silas W Smith
Jun 28, 2011·Arhiv za higijenu rada i toksikologiju·Anita BosakZrinka Kovarik
Jan 31, 2012·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Miroslav Pohanka
Nov 19, 2013·The Journal of Pharmacy and Pharmacology·Brígida R PinhoPaula B Andrade
Mar 10, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Qiong XieZhuibai Qiu
Apr 17, 2012·Natural Product Reports·Malte GerschStephan A Sieber
Sep 14, 2019·Future Medicinal Chemistry·Adebayo A Adeniyi, Jeanet Conradie
Jan 23, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Benoit DavidHolger Gohlke

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