Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors
Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors
复制标题
基于多个药效团的虚拟筛选、对接和分子动力学模拟方法发现新型HPPD抑制剂
DOI：
10.3390/ijms21155546
复制
发表时间：
2020-08-01
影响因子：
5.6
通讯作者：
Ye, Fei
中科院分区：
文献类型：
--
作者：
Fu, Ying;Ye, Tong;Ye, Fei
4-羟基苯基丙酮酸双加氧酶（HPPD）是一种铁依赖性非血红素加氧酶，参与酪氨酸的分解代谢途径，是4-羟基苯基丙酮酸转化为尿黑酸的重要酶，因此被认为是除草剂的靶标。在这项研究中，开发了一套基于多种结构的 HPPD 抑制剂药效团模型。对ZINC和天然产物数据库进行虚拟筛选，得到29个化合物。通过分子对接研究获得的HPPD与其抑制剂的结合模式表明，Phe424、Phe381、His308、His226、Gln307和Glu394残基对于活性至关重要。分子力学广义出生表面积 (MM/GBSA) 结果表明，库仑力、亲脂性和范德华 (vdW) 相互作用对结合亲和力做出了主要贡献。这些努力将极大地有助于设计新型有效的 HPPD 抑制性除草剂。
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an iron-dependent non-heme oxygenase involved in the catabolic pathway of tyrosine, which is an important enzyme in the transformation of 4-hydroxyphenylpyruvic acid to homogentisic acid, and thus being considered as herbicide target. Within this study, a set of multiple structure-based pharmacophore models for HPPD inhibitors were developed. The ZINC and natural product database were virtually screened, and 29 compounds were obtained. The binding mode of HPPD and its inhibitors obtained through molecular docking study showed that the residues of Phe424, Phe381, His308, His226, Gln307 and Glu394 were crucial for activity. Molecular-mechanics-generalized born surface area (MM/GBSA) results showed that the coulomb force, lipophilic and van der Waals (vdW) interactions made major contributions to the binding affinity. These efforts will greatly contribute to design novel and effective HPPD inhibitory herbicides.