基于靶蛋白共结晶药效团与分子对接的新型WEE1抑制剂的设计  

Design of a novel WEE1 inhibitor based on target protein co-crystal pharmacophores and molecular docking

作　　者：和龙 罗小娇 刘新琦 温晓燕 王玲 欧阳亮[2] 何俊[2] HE Long;LUO Xiaojiao;LIU Xinqi;WEN Xiaoyan;WANG Ling;OUYANG Liang;HE Jun(Beijing Funhau Medicine Technology Co.,Ltd.Beijing,102600 P.R.China;State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Chengdu,Sichuany 610041 P.R.China;College of Basic Medical,Jilin University,Changchun Jilin,130012 P.R.China)

机构地区：[1]北京宽厚医药科技有限公司,北京102600 [2]四川大学华西医院生物治疗国家重点实验室,四川成都610041 [3]吉林大学基础医学院,吉林长春130012

出　　处：《华西药学杂志》2020年第2期144-148,共5页West China Journal of Pharmaceutical Sciences

基　　金：四川省应用基础研究项目(2019YJ0108);北京市科协金桥工程种子资金项目(ZZ19015)。

摘　　要：目的通过药效团和分子对接方式设计WEE1抑制剂。方法使用Discovery Studio 3.1建立WEE1蛋白小分子共晶复合物药效团,并利用活性、非活性化合物验证药效团的识别能力,筛选出最佳药效团模型。用筛选出的最佳药效团模型筛选化合物库,然后,分子对接进一步筛选出有效的先导化合物。结果根据验证结果筛选出区分活性和非活性化合物能力强的药效团模型ADDHHP,并用于小分子库筛选;通过分子对接研究,发现化合物含有磺胺基和氨基,与氨基酸残基有较好的亲和力,且含有氢键数目多。结论根据药效团和分子对接结果所得的化合物有助于WEE1抑制剂分子的设计、改构、并为发现治疗癌症的强有力的先导化合物提供了指导。OBJECTIVE To design novel WEE1 in hibitor.METHODS Discovery Studio 3.5 was used to establish pharmacophore and perform molecular docking.Based on validation results,the best pharmacophore picked out to screen library,followed by docking.RESULTS It was found that the compounds contained Sulfonamide groups and amino groups,which showed more conjugated hydrogen bonds during molecular docking,possessed a better affinity.CONCLUSION Leads selected out on basis of pharmacophores and molecular docking results contribute to the design,modification,and guidance of the discovery of powerful lead compounds for the treatment of cancer.

关 键 词：WEE1抑制剂 药效团 药物筛选 分子对接 抗肿瘤 细胞周期 Decoy验证 先导化合物 

分 类 号：R914[医药卫生—药物化学]