基于药效团和分子对接筛选D-丙氨酰-D-丙氨酸连接酶抑制剂

High-throughput Virtual Screening of D-alanyl-D-alanine Ligase Inhibitors Based on Pharmacophore and Molecular Docking

试图通过虚拟筛选来发现具有抑制D-丙氨酰-D-丙氨酸连接酶(D-alanine-D-alanine ligase,Ddl)潜力的新结构类型抗生素。以活性较强的Ddl抑制剂作为训练集,使用Discovery Studio软件中的HipHop模块构建10个药效团,以性能最好的药效团对Specs化合物库进行虚拟筛选,然后通过LibDock进行基于分子对接(PDB ID:1IOW)的筛选。结果表明,high_active_08模型预测性能最佳,该模型含有2个氢键受体和3个氢键供体共5个药效团特征元素。用药效团模型、分子对接对Specs库进行高通量筛选,通过结合模式分析最终从约21万化合物库中得到34个化合物,经过分子聚类确定11个有潜力且与药效团匹配度高的多样性Ddl小分子抑制剂。high_active_08药效团模型可以筛选出具有Ddl抑制潜力的结构新颖的抗菌化合物。

New structural antibiotics with potential to inhibit D-alanine-D-alanine ligase(Ddl)were identified by virtual screening.Using Ddl inhibitors with high activity as the training set,10 pharmacophores were constructed by using Discovery Studio software based on the HipHop of small ligand molecules,the best pharmacophore was used for virtual screening of Specs compound library,and then the molecular docking based(PDB ID:1IOW)screening was performed by LibDock.The results showed that the high_active_08 model had the best prediction performance,which contained altogether 5 pharmacophore characteristic elements including 2 hydrogen bond acceptors and 3 hydrogen bond donors.The pharmacophore model and molecular docking were used for high-throughput screening of the Specs library.In the end,34 compounds were obtained from the library of about 210000 compounds by binding pattern analysis.After molecular clustering,11 Ddl small molecule inhibitors with potential and high matching degree to pharmacophore were also identified.It is concluded that the high_active_08 pharmacophore model has the potential to screen for structurally novel antimicrobial compounds with Ddl inhibition potential.