基于从头设计及ADMET的木姜子属中木脂素类化合物5-LOX抑制剂筛选研究(Ⅱ)  

Screening of 5-LOX inhibitors of lignans in Litsea based on de novo evolution and ADMET(Ⅱ)

作　　者：夏侯真如 汪欣怡 潘捷 杨平[1] 李碧桃[3] 文政琦[3] 汪云松[1] 杨靖华[1] XIA-HOU Zhen-ru;WANG Xin-yi;PAN Jie;YANG Ping;Li Bi-tao;WEN Zheng-qi;WANG Yun-song;YANG Jing-hua(Key Laboratory of Medicinal Chemistry for Natural Resource,Ministry of Education,Yunnan Provincial Center for Research&Development of Natural Products,School of Chemical Science and Technology,Yunnan University,Kunming 650091,Yunnan,China;School of Basic Medical Science,Kunming Medical University,Kunming 650500,Yunnan,China;First Affiliated Hospital of Kunming Medical University,Kunming 650500,Yunnan,China)

机构地区：[1]云南大学教育部自然资源药物化学重点实验室,云南省天然产物转化与应用重点实验室,化学科学与工程学院,云南昆明650091 [2]昆明医科大学基础医学院,云南昆明650500 [3]昆明医科大学第一附属医院,云南昆明650500

出　　处：《云南大学学报（自然科学版）》2022年第4期800-811,共12页Journal of Yunnan University(Natural Sciences Edition)

基　　金：国家自然科学基金(82160661,81960629,21662040);云南省科技厅创新团队(202005AE160005)。

摘　　要：5-脂氧合酶(5-LOX)作为白三烯生物合成的关键酶之一,是炎症反应研究中的重要靶点.目前其相关上市药物存在肝毒性、半衰期短等不足,因此肝毒性较小且抑制活性较高的5-LOX抑制剂具有开发研究的必要.文章在前期研究基础上,发现传统药物资源木姜子属植物中的木脂素类化合物可能具有一定的5-LOX抑制活性,因此采用从头设计、类药规则和ADMET筛选等计算机辅助药物设计技术,对其进行深入研究.研究发现从头设计碎片生长分子均有较好的筛选结果,且其中有11个小分子,分子对接打分值较高,残基结合模式与齐留通较为类似,特别是其具有肝毒性较小、血浆蛋白结合率较低的优势特性.研究结果显示木姜子属植物中木脂素类化合物的11个从头设计衍生小分子具有一定的潜在5-LOX抑制活性,且具有肝毒性较小、血浆蛋白结合率较低的优势,具有一定深入研究价值,并且通过对残基相互作用模式的分析,为后续研究提供了一定的参考.Lipoxygenase-5(5-LOX),as one of the key enzymes for leukotriene synthesis,is an important target in the study of inflammatory response.At present,most of the related marketed drugs have the disadvantages of hepatotoxicity and short half-life,so it is necessary to develop and study the 5-LOX inhibitor with low hepatotoxicity and high inhibitory activity.Based on the previous studies,it was found that the lignans in the traditional medicinal resource Litsea plants might have certain 5-LOX inhibitory activity.Therefore,de novo evolution,drug-like rule and ADMET screening and other computer-aided drug design techniques were adopted for in-depth study.It is found that all the molecules grown from de novo design fragments have good screening results.Among them,11 small molecules had higher molecular docking scores and their residue binding patterns were similar to zileuton’s.In particular,they had the advantages of low hepatotoxicity and low plasma protein binding rate.The results showed that the 11 small molecules obtained by de novo design of lignan compounds in Litsea plants had certain potential 5-LOX inhibitory activity,and had the advantages of low hepatotoxicity and low plasma protein binding rate,which had certain in-depth research value.And through the analysis of the interaction of residues,it provided some reference for the follow-up research.

关 键 词：木姜子属 木脂素 5-LOX抑制剂 从头设计 ADMET筛选 

分 类 号：O629.34[理学—有机化学]