中文摘要
发现全新结构先导或潜在新作用靶标，是新农药创制的核心。昆虫神经肽是影响昆虫生长发育、变态等过程的一类重要生理活性物质，是开发新型IGRs的潜在先导。本项目首次选择德国小蠊抑咽侧体素(AS-A)中片段最短的肽BLAST-I作为先导，对其核心片断中的特征β-转角，采用模拟肽学中的β-转角模拟技术进行结构模拟获得14个β-转角模拟物；以核心五肽为先导，先后设计合成N端、C端及中间转角模拟共41个新型模拟肽类化合物、20个非肽类化合物。以德国小蠊咽侧体为靶标，通过生物学评价获得肽模拟物的离体活性数据和部分化合物的活体活性数据。以32个AST模拟物为对象，进行了HQSAR研究，得到了具有很好预测能力的HQSAR模型。对太平洋折翅蠊AST受体序列进行了初步同源模建研究，通过分子对接得出AST 5及类似物与AST受体的可能结合模型，提出了活性AST模拟物所需要满足的结构通式。发现2个有活体活性且具进一步研究价值的IGRs先导化合物。本课题研究对发现具结构全新的模拟肽类IGRs先导提供实验和理论依据。研究成果对增强我国IGRs源头创新的能力和提高我国农药自主创新的水平有重要意义.
英文摘要
To discover novel lead compounds and targets is the core of the new pesticide discovery. Neuropeptides can control the most critical metabolic, homeostatic, developmental, reproductive and behavioural events during an insect's life. They are regarded as the new leads of IGRs. Therefore,corpora allata (CA)was chosen as the target and the smallest peptide,allatostatins(BLAST-I), was selected as hit in this research. 14 β-turn mimetics were first designed and synthesized by replacing the β-turn in the core sequence of BLAST-I with Tic,Aic and Pro groups. Fifteen analogues which mimicked each amino acid of the core region,pentapeptide(YDFGL),were secondly designed and synthesized.The results suggest that the sequence FGLa is more important than Y/FX since Y/FX mimics show strong effects in vitro and in vivo. 25 novel N-terminal analogs of pentapeptide were further designed and synthesized. Amound them,K15 has better activity than most natural Dippu-ASTs. A predictable and statistically meaningful HQSAR model of 32 AST analogs (28 as training sets and 4 as test sets) was obtained. The molecular modeling of receptor and docking between analogues and receptor was also priliminarly studied. Based on the structure-activity relationship of pentapeptide analogues, a general structure of potential potent AST analogues is proposed here. This research work will provide good clue for discovering novel peptide-like leads of IGRs. The research fruits are useful to the innovation of our national pesticide discovery.
结题摘要
发现全新结构先导或潜在新作用靶标，是新农药创制的核心。昆虫神经肽是影响昆虫生长发育、变态等过程的一类重要生理活性物质，是开发新型IGRs的潜在先导。本项目首次选择德国小蠊抑咽侧体素(AS-A)中片段最短的肽BLAST-I作为先导，对其核心片断中的特征β-转角，采用模拟肽学中的β-转角模拟技术进行结构模拟获得14个β-转角模拟物；以核心五肽为先导，先后设计合成N端、C端及中间转角模拟共41个新型模拟肽类化合物、20个非肽类化合物。以德国小蠊咽侧体为靶标，通过生物学评价获得肽模拟物的离体活性数据和部分化合物的活体活性数据。以32个AST模拟物为对象，进行了HQSAR研究，得到了具有很好预测能力的HQSAR模型。对太平洋折翅蠊AST受体序列进行了初步同源模建研究，通过分子对接得出AST 5及类似物与AST受体的可能结合模型，提出了活性AST模拟物所需要满足的结构通式。发现2个有活体活性且具进一步研究价值的IGRs先导化合物。本课题研究对发现具结构全新的模拟肽类IGRs先导提供实验和理论依据。研究成果对增强我国IGRs源头创新的能力和提高我国农药自主创新的水平有重要意义.