黄嘌呤氧化酶靶向小分子抑制剂的虚拟筛选

Virtual screening of xanthine oxidase targeted small molecule inhibitors

为了挖掘生物活性高、靶点明确的新型抗痛风药物先导化合物,以黄嘌呤氧化酶(xanthine oxidase,XOD)为靶标虚拟筛选小分子抑制剂.从PDB数据库下载XOD蛋白晶体结构,经Schrodinger 2018中的“Protein prepara-tion wizard”模块预处理,基于XOD活性口袋与小分子配体作用方式特征构建了3个药效团,对FDA数据库和Chemdiv数据库进行分子对接筛选.结果发现:以非布索坦与XOD对接分数-35.790 kJ/mol为阈值,筛选得到低于该分数的化合物共206个.通过类药五原则以及ADMET分析,发现有8个化合物具有较好的成药性.将此8个化合物进行结合自由能计算,其中氟芬那酸、罗索沙星、化合物6(CAS:400076-03-1,苯并吡唑类化合物)和化合物7(CAS:866050-17-1,酞嗪类化合物)与阳性对照组非布索坦的作用方式相似,能与黄嘌呤氧化酶形成稳定性较强的复合物,可作为潜在的黄嘌呤氧化酶抑制剂.

To discover new lead compounds with high biological activity and specific target for anti-gout drugs,xanthine oxidase(XOD)was used as the target to screen small molecule inhibitors.XOD protein crystal structures were downloaded from PDB database and preprocessed by“Protein preparation wizard”module in Schrodinger 2018.Three pharmacophore were constructed based on the characteristics of XOD active pocket and small molecule ligand action mode.The FDA database and Chemdiv database were screened for molecular docking.The results showed that using febuxostat and XOD docking fraction(-35.790 kJ/mol)as the threshold,206 compounds below the fraction were selected.Through the five principles of drug class and ADMET analysis,it was found that eight compounds had good druggability.The binding free energies of these eight compounds were calculated.Among them,flufenamic acid,roxoxacin,compound 6(CAS:400076-03-1,benzopyrazole compound)and com-pound 7(CAS:866050-17-1,phthalazine compound)acted in a similar way to febuxostat in the positive control group,which can form stable complexes with xanthine oxidase.These results indicated that the four compounds could be the potential xanthine oxidase inhibitors.