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目的:构建SARS病毒类3C(3CL)蛋白酶的三维结构模型,根据这一模型设计3CL蛋白酶的抑制剂。方法:用生物信息学方法从GenBank和PDB库中搜寻出具有晶体结构并与SARS病毒3CL蛋白酶有较高同源型的蛋白质,以此为模板,用同源蛋白模建方法构建SARS病毒3CL蛋白酶的三维结构模型;针对模建的三维结构模型,进行高通量虚拟筛选,从现有小分子数据库中获得具有抑制SARS病毒3CL蛋白酶活性的化合物。结果:同源性分析表明SARS病毒3CL蛋白酶与遗传性肠胃炎主蛋白酶(TGEV M~(pro)),有较高的同源性,组成底物结合口袋残基的同源性更高。因此,可以根据TGEV M~(pro)的晶体结构为模板模建SARS病毒3CL蛋白酶的三维结构。 三维结构模型表明,ARS病毒3CL蛋白酶的结构与TGEV M~(pro)的结构非常相象,两个蛋白酶活性口袋的结构和形状儿乎一样。虚拟筛选测试研究表明,MRRD数据库中的73个蛋白酶抑制剂能与两个蛋白同时作用。结论:无论是SARS病毒3CL蛋白酶还是TGEV M~(pro)的晶体结构均可以作为设计抗SARS药物的结构模型。从现有的蛋白酶抑制剂中筛选抗SARS药物可能是一条好的途径。
OBJECTIVE: To construct a 3D structural model of SARS virus 3C (3CL) protease, and to design an inhibitor of 3CL protease according to this model. METHODS: Bioinformatics methods were used to search out the proteins with the crystal structure and high homology with SARS virus 3CL protease from GenBank and PDB library. Using this as a template, the 3-dimensional proteome of SARS virus 3CL was constructed by homologous protein modeling Structure model. According to the three-dimensional model of the model construction, high-throughput virtual screening was carried out to obtain the compound having the activity of inhibiting the 3CL protease of the SARS virus from the existing small molecule database. Results: Homology analysis showed that the SARS virus 3CL protease has high homology with the genetic predominant gastroenteritis major protease (TGEV M ~ (pro)), and the homology of the substrate binding pocket residues is higher. Therefore, the three-dimensional structure of SARS virus 3CL protease can be modeled according to the crystal structure of TGEV M ~ (pro). The three-dimensional structural model shows that the structure of ARS virus 3CL protease is very similar to the structure of TGEV M pro, and the structure and shape of the two protease active pockets are almost the same. A virtual screening test showed that 73 protease inhibitors in the MRRD database were able to work with both proteins simultaneously. Conclusion: Both the crystal structure of SARS virus 3CL protease and TGEV M ~ (pro) can be used as a structural model for the design of anti-SARS drugs. Screening for anti-SARS drugs from existing protease inhibitors may be a good way to go.