Abstract:
Current studies on Anopheles anticholinesterase insecticides are focusing on identifying
agents with high selectivity towards Anopheles over mammalian targets. Acetylcholinesterase (AChE) from electric eel is often used as the bioequivalent enzyme to study ligands
designed for activity and inhibition in human. In this study, previously identified derivatives
of a potent AChE, donepezil, that have exhibited low activity on electric eel AChE were
assessed for potential AChE-based larvicidal effects on four African malaria vectors; An.
funestus, An. arabiensis, An. gambiae and An. coluzzii. This led to the identification of four
larvicidal agents with a lead molecule, 1-benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2
showing selectivity for An. arabiensis as a larvicidal AChE agent. Differential activities of this
molecule on An. arabiensis and electric eel AChE targets were studied through molecular
modelling. Homology modelling was used to generate a three-dimensional structure of the
An. arabiensis AChE for this binding assay. The conformation of this molecule and corresponding interactions with the AChE catalytic site was markedly different between the two
targets. Assessment of the differences between the AChE binding sites from electric eel,
human and Anopheles revealed that the electric eel and human AChE proteins were very
similar. In contrast, Anopheles AChE had a smaller cysteine residue in place of bulky phenylalanine group at the entrance to the catalytic site, and a smaller aspartic acid residue at
the base of the active site gorge, in place of the bulky tyrosine residues. Results from this
study suggest that this difference affects the ligand orientation and corresponding interactions at the catalytic site. The lead molecule 2 also formed more favourable interactions with
An. arabiensis AChE model than other Anopheles AChE targets, possibly explaining the
observed selectivity among other assessed Anopheles species. This study suggests that 1-
benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2 may be a lead compound for designing
novel insecticides against Anopheles vectors with reduced toxic potential on humans.
Description:
DATA AVAILABILITY STATEMENT : Amino acid sequence
data are available UniProt Knowledge Base
(Accession numbers: A0A182HKN4, A0A6E8V9T9,
and A0A182RZ85). The 3D molecular structure
data are available on Protein Data Bank (https://
www.rcsb.org/) with the ID numbers: 5YDI, 5YDH,
1EVE, and 4EY7.