在烟草和人源PPO之间具有高选择性的新型PPO抑制剂的合理设计

Protoporphyrinogen oxidase herbicides, which contain high efficiency, low toxicity, environmentally-friendly features, have been one of the hottest research areas in the fields of herbicide development in recent decades. However, people generally focus on the herbicidal in the field did not consider the selective between tobacco and mammals PPO. Hence, Very few high selective PPO herbicides are known to date, many of which are less selective or nonselective with respect to mammalian PPO. It might be causing some damage in mammals for long-term use nonselective herbicide. Therefore, the design of highly selective PPO inhibitors between tobacco and human PPO has thus far proved to be quite significant. The project intends to tobacco as a model organism, we combine with organic synthesis, molecular modeling and molecular biology techniques to study the mechanism of inhibitors interaction with tobacco and human PPO, revealing the molecular mechanism of selectivity. On this basic, through molecular docking, molecular modeling and virtual screening method for the rational design of inhibitors, which has ultra-high selectivity between tobacco and human PPO. We have building the foundation for the development of high selectivity , high activity and low toxicity herbicides.

原卟啉原氧化酶除草剂因其高效、低毒、环境友好等特点成为除草剂领域近几十年研究的热点。然而，人们在研究中通常只注重除草效果并没有考虑对哺乳动物源PPO的选择性。因此，绝大多数的PPO除草剂对于哺乳动物源的PPO只有较低甚至没有选择性。长期使用不具有选择性的除草剂极有可能对哺乳动物特别是人体造成一定的伤害。因此，设计合成出在植物源与人源PPO之间具有高选择性的除草剂具有十分重要的实际意义。本项目拟以烟草为模式生物，将有机合成技术，分子模拟技术与分子生物学技术进行有机结合，深入研究抑制剂与不同来源的PPO之间的相互作用，揭示抑制剂分子产生选择性的分子机制。在此基础上，通过分子对接、分子模拟、虚拟筛选等方法合理的设计出在烟草与人源PPO之间具有高选择性的抑制剂。为开发高选择性、高活性、低毒副作用的除草剂奠定基础。

“高效、低毒、环境友好”是现代农药研究的方向。以原卟啉原氧化酶（PPO）作为靶标的除草剂因此受到人们广泛的关注，并成功开发出八种结构类型共29个商品化除草剂。然而，该类除草剂在开发中往往只注重活性的提升并没有考虑到对人体造成伤害的潜在可能性。因此本项目对比烟草PPO与人体PPO活性空腔结构，通过类同合成(Me Too)策略、基于靶标三维结构、计算机辅助药物分子策略这三种方法开展对在烟草和人体PPO具有高度选择性的新型PPO抑制剂进行合理的设计。在我们所设计的嘧啶二酮，氯酞亚胺，苯基吡唑和哒嗪酮四大结构类型中，数个化合物展示出在烟草PPO与人体PPO之间良好的选择选择性。特别是氯酞亚胺系列中，化合物II-8b, II-8g, II-8k, II-8l, II-8n, II-9b, II-9c, II-9d, II-9f 对人体PPO无抑制活性。该项目揭示了抑制剂在烟草PPO与人体PPO之间产生选择性的分子机理。针对烟草PPO结构开展基于药效团的虚拟筛选农药分子设计，获得具有高选择性、高活性、结构新颖的PPO抑制剂提供理论依据。