engleski

Modulating cholinesterases activity by quinuclidine and cinchona-based compounds

Antidotes for organophosphorus poisoning are oximes, which antidotal properties are related to their ability to reactivate phosphorylated acetyl- cholinesterase (AChE, EC 3.1.1.7), and butyrylcholinesterase (BChE, EC 3.1.1.8) when used as scavenger [1]. In addition, it is well known that the protection of cholinesterases (ChEs) from phosphorylation can be achieved by the previous inhibition with carbamates. Given that there is no single compound applicable as antidote for poisoning with various organophosphorus agents, pursue for compounds with better chemical, physical and biochemical properties as well as better understanding of their interactions with both enzymes are still important. Therefore, over the years, a series of novel quinuclidine and cinchona-based oximes and carbamates were synthesized to be evaluated as inhibitors and/or reactivators of phosphorylated human ChEs [2, 3]. Compounds were modified to gain divers structures and the hybrid molecules with known aromatic pyridine and imidazole oximes designed. Activity and selectivity of cholinesterases were described, and to clarify differences in the inhibition and oxime reactivation potency, conformational analysis of compounds as well as detailed docking studies were conducted. Orientations of studied compounds in the active site of ChEs have been proposed by QM/QM studies. Analyses of the obtained complexes pointed out significant hydrogen bonds and close contacts between functional groups of compounds and the residues of the active site. To facilitate the prediction and design of new and more potent compounds, the most optimal regression models for the prediction of bioactivity were established and validated by extensive machine learning protocols. (Supported by the Croatian Science Foundation, Project No. IP-2016-06-3775 ADESIRE)

cholinesterase ; cinchona-based compounds ; quinuclidine compounds ; inhibition ; oxime reactivation potency

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