Journal
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
Volume 59, Issue 7, Pages 2918-2922Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jf102523s
Keywords
neonicotinoid; neonicotinoid pharmacophore; nicotinic acetylcholine receptor; receptor structure-guided insecticide design
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Neonicotinoid agonists with a nitroimino pharmacophore are used worldwide for crop protection and animal health care. Chemical and structural biology investigations on the nicotinic acetylcholine receptor structure in the neonicotinoid-bound state revealed a unique niche beyond the nitro oxygen tip toward the loop D subsite. The nitroimino pharmacophore can be replaced to suitably fit the newly recognized cavity by acylimino [=NC(O)R] and phenoxycarbonylmino [=NC(O)OPh] variants. The =NC(O)R analogues, where R is a hydrogen acceptor pyridine, pyrazine, or trifluoromethyl, showed high receptor potency, suggesting that the extended pharmacophore undergoes hydrogen bonding with the loop D Arg basic residue. The =NC(O)OPh analogues had appreciably higher affinity with an electron-donating substituent on the phenyl ring than with an electron-withdrawing group, predicting that the benzene plane and loop D Trp indole form a face-to-edge aromatic interaction. These studies illustrate strategic ligand design combining the chemorational approach with the three-dimensional receptor structure.
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