Zhao Shan-Shan, Wang Yu-Jie, Tang Lei, Guo Bing, Wang Ling, Zhang Ji-Quan, Yang Sheng-Gang
College of Pharmacy, Guizhou Medical University Guiyang 550025 China
Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D Guiyang 550025 China.
RSC Adv. 2023 Apr 5;13(16):10873-10883. doi: 10.1039/d2ra08006k. eCollection 2023 Apr 3.
Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a value of 2.21 μM for PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.
原卟啉原氧化酶（PPO）是叶绿素和血红素生物合成中的关键酶，其抑制剂的开发在制药和农药行业都具有重要意义。然而，目前开发的PPO抑制剂生物选择性不显著，对非靶标生物有严重影响。在本研究中，采用基于对接的虚拟筛选方法结合生物活性测试来获得新型PPO选择性抑制剂。生物活性测试结果表明，13种化合物对人PPO具有10倍的选择性。最佳选择性化合物ZINC70338对PPO的IC50值为2.21 μM，对人PPO的选择性大于113倍。然后通过分子动力学模拟分析ZINC70338在不同物种PPO中的选择性机制，为新型选择性抑制剂的设计提供设计依据和理论指导。
