Molecular similarity analysis between insect juvenile hormone and N,N-diethyl-m-toluamide (DEET) analogs may aid design of novel insect repellents

Molecular similarity analysis of stereoelectronic properties between natura l insect juvenile hormone (JH), a synthetic insect juvenile hormone mimic ( JH-mimic, undecen-2-yl carbamate), and N,N-diethyl-m-toluamide (DEET) and i ts analogs reveals similarities that may aid the design of more efficacious insect repellents and give a better insight into the mechanism of repellen t action. The study involves quantum chemical calculations using the AM1 se mi-empirical computational method enabling a conformational search for the lowest and most abundant energy conformers of JH, JH-mimic, and 15 DEET com pounds, followed by complete geometry optimization of the conformers, Simil arity analyses of stereoelectronic properties such as structural parameters , atomic charges, dipole moments, molecular electrostatic potentials, and h ighest occupied molecular orbital (HOMO) and lowest unoccupied molecular or bital (LUMO) energies were performed on JH, JH-mimic and the DEET compounds . The similarity of stereoelectronic attributes of the amide/ester moiety, the negative electrostatic potential regions beyond the van der Waals surfa ce, and the large distribution of hydrophobic regions in the compounds appe ar to be the three important factors leading to a similar interaction with the JH receptor. The similarity of electrostatic profiles beyond the van de r Waals surface is likely to play a crucial role in molecular recognition i nteraction with the JH receptor from a distance, This also suggests electro static bioisosterism of the amide group of the DEET compounds and JH-mimic and, thus, a model for molecular recognition at the JH receptor, The insect repellent property of the DEET analogs may thus be attributed to a conflic t of complementarity for the JH receptor binding sites. Copyright (C) 2000 John Wiley & Sons, Ltd.