新型Mer酪氨酸激酶抑制剂核心骨架的虚拟筛选

Discovery of new core scaffold of Mer tyrosine kinase selective inhibitors by virtual screening

目的发现一系列新型选择性Mer酪氨酸激酶抑制剂(TKI)的母核结构,并依据其设计化合物。方法分别利用3个已发表的Mer TK及配体(化合物1、2和3)的复合晶体结构(PDB code:3TCP,4MHA和4M3Q),由ZINCPharmer来产生只包含配体核心区域的药效团模型,并对ZINC化合物库进行筛选。筛选结果经过分析、归类,得到新型母核结构,据其设计化合物,并利用分子对接技术对设计化合物进行初步评价。结果药效团筛选得到含有16 253个化合物的数据集,归类为12种核心结构,它们可以和关键氨基酸形成相互作用的原子或基团。其中,化合物12将疏水脂肪链含于芳环中,结构变化较大,依据其设计了化合物16a^16d,分子对接发现16c评分最高,可作为进一步理性设计的基础。结论本研究通过基于药效团模型的虚拟筛选方法,发现了一系列选择性Mer TKI母核结构的替代物,它们保持了选择性抑制剂与靶点的关键作用,可应用于新化合物的设计中。同时,此方法也可用于其他靶标药物的发现中。

Objective To discover the core structures for a series of new selective Mer tyrosine kinase inhibitors（TKI ） and design their compounds accordingly. Method The pharmacophore of the core domain was respectively generated by cocrystal of Mer tyrosine kinase （Mer TK） and bound inhibitors 1 （UNC569）, 2 and 3 （PDB code： 3TCP, 4MHA and 4M3Q） and used to proceed virtual screening with online platform ZINCPharmer. Core structures were obtained after analyzing and classifying the virtual screening results and used for new inhibitors design. Results Totally 16 253 compounds were screened out, and classified to 12 core structures. Based on structure 12, 16a-16d were designed and docked with Mer TK. Among them, 16c exhibited the lowest binding energy, which could be used for future drug design. Concludsion A series of core structures keeping critical interaction with Mer TK are discovered and can be used for the new selective Mer TKI design and development. The procedure can also be applied to other targets drug discovery.