コンピュータによる農薬の分子設計および構造活性相関
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概要
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Recent developments of computational techniques such as theoretical calculations and computer graphics are providing tools for designing bioactive molecules. My coleagues and I have applied computational technique and quantitative structure-activity relationships (QSAR) to study on structure-activity profiles of insect juvenile hormone (JH) mimics and fungicidal imidazoles. In the QSAR analyses steric and hydrophobic properties were important for the JH activity of mimics having a 2, 4-dodicadienoate structure against Aedes aegypti and Tenebrio molitor. The steric and hydrophobic parameters in the analyses suggested strong effects of steric dimensions such as molecular length and shape on the JH activity. The optimum hydrophobicity was ca. 6.8 in terms of log P value. Based on the results of QSAR, various compounds having a terpenoid component were synthesized, among which some undecen-2-one oxime O-ethers and undecen-2-yl carbamates showed JH activity against Culex pipiens, Chilo suppressalis and Musca domestics. Replacement of the terpenoid component in the oxime O-ethers by diphenylether structure produced novel JH mimics as active as methoprene. In the conformational analyses and computer graphics studies the diphenyl-ether derivatives and the terpenoid compounds were superimposable in stable conformations. Besides the superimposability, functional groups in the JH mimics had similar electrostatic properties in terms of electrostatic potentials. In the QSAR of triflumizole and related fungicidal imidazoles, steric, electronic and hydrophobic effects of substituents on the benzene ring were important for the fungicidal activity against cucumber powdery mildew. The effects of substituents on the imino carbon were expressed by steric and hydrophobic parameters as well as some indicator variables. Conformational analysis and computer graphics were employed to study the mode of interaction of triflumizole with cytochrome P-450, the target enzyme of fungicidal azoles. An energy minimum structure of triflumizole fitted the cavity of cytochrome P-450 so as to block the oxidation of lanosterol, the ergosterol precursor. The results of QSAR coincided with the computer graphics model with respect to steric and hydrophobic properties, showing that the physicochemical properties expressed by the parameters in QSAR were important to antagonize cytochrome P-450 and thus to inhibit the biosynthesis of ergosterol.
- 日本農薬学会の論文
- 1990-08-20
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