基于结构的肽脱甲酰基酶抑制剂的虚拟筛选及活性研究

Structure-based virtual screening of peptide deformylase inhibitors and biological activity research

目的通过计算机虚拟筛选寻找肽脱甲酰基酶(Peptide deformylase,PDF)的小分子抑制剂。方法从PDB(Protein Data Bank)数据库中获得与肠球菌(Enteroccous faecium)PDF序列相似性最高的肺炎链球菌PDF的X-射线衍射晶体结构,应用Sybyl7.3软件中的Sur?ex-Dock对我室微生物天然产物数据库(Microbial Natural Products Database,MNPD)中约15000个样品进行虚拟筛选;采用高通量荧光检测法和微稀释法分别测定虚拟筛选获得的部分高得分化合物对PDF酶的抑制作用和抗菌活性。结果应用Surflex-Dock虚拟筛选获得得分达5.17及以上的命中化合物651个,经综合分析,挑选出其中5个化合物进行进一步的体外生物学活性研究,结果表明,1个化合物(spergualin)有一定的PDF抑制活性和抗菌活性,其它4个化合物仅有弱活性或无活性。结论发现化合物spergualin具有一定的PDF抑制活性和抗耐药表皮葡萄球菌活性。证实了计算机虚拟筛选与实物筛选相结合可明显提高PDF酶抑制剂的筛选效率。

Objective To discover peptide deformylase （PDF） inhibitors by Structure-based virtual screening. Methods PDF X-ray diffraction crystal structure of streptococcus pneumoniae, which had the highest similarity with Enteroccous faecium PDF in known crystal structure, was obtained from Protein Data Bank. Structure-based virtual screening of 15000 compounds from Microbial Natural Products Database（MNPD） was performed by surflex- dock of Sybyl7.3 software. Some of high score compounds were pick out to determine their inhibitive activity on PDF and antibacterial activities by high-throughput fluorescence detection and micro dilution respectively. Results 651 compounds with score 5.17 and over it were ranked through surflex-dock virtual screening. Among them, 5 compounds were selected for biological active detection. The results showed that spergualin had inhibitive activity on PDF and antibacterial activity and other 4 compounds with weak or no activity. Conclusion The inhibitive activity on PDF and anti-MRSE activity of spergualin was discovered. The combination of virtual screening and entity screening can improve significantly efficiency of PDF inhibitors discovery.