DETERMINATION OF IVERMECTIN ALLOSTERIC INTERACTION PATTERNS WITH GLUTAMATE-GATED CHLORIDE CHANNEL OF CAENORHABDITIS ELEGANS

Abstract

This study aimed to determine the structural patterns of ivermectin, a compound with anthelmintic and insecticidal activity, in its allosteric interactions with the α-homopentameric glutamate-gated chloride channel of Caenorhabditis elegans. The findings reveal that the binding site primarily consists of hydrophobic, aliphatic, polar, and small residues. The macrocyclic lactone ring exhibits a high affinity for the V—I—G—A—M pattern, involving residues V278, I280, G281, A282, and M284 of the M3 subunit of the (+) configuration, as well as the I—V—D—L pattern, encompassing residues I273 of the M2-M3 region, D277, V278 of the M3 subunit of the (+) configuration, and L218 of the M1 subunit (—) configuration. The spiroketal group interacts with the M—T—F— C—M—I pattern, comprising residues M284, T285, and F288 of the M3 subunit of the (+) configuration, and C225, M226, and I229 of the M1 subunit (—) configuration. Regarding the benzofuran group, it predominantly interacts quantitatively with small and polar residues. However, it exhibits fewer contacts with hydrophobic residues compared to the other groups. This is evident in the T—A—S—N—D—I—L—Q—I—P pattern, involving residues T257, A258, S260, N264, D277, and I280 of the M3 subunit of the (+) configuration, and L218, Q219, I222, and P223 of the M1 subunit (—) configuration. The obtained data can be utilized to identify new molecular targets for ivermectin and facilitate the development of new ligands with high affinity for the identified ivermectin targets in various eukaryotic organisms.