Identification of type I and type II inhibitors of c-Yes kinase using in silico and experimental techniques
Identification of type I and type II inhibitors of c-Yes kinase using in silico and experimental techniques
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DOI：
10.1080/07391102.2017.1329098
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Gromiha, M. Michael
中科院分区：
文献类型：
--
作者：
Ramakrishnan, Chandrasekaran;Thangakani, Anthony Mary;Gromiha, M. Michael
c-Yes激酶被认为是抗肿瘤药物设计的有吸引力的靶点之一。存在于大多数激酶中的DFG（Asp-Phe-Gly）基序将采用活性和非活性构象，称为DFG-in和DFG-out，并且它们的抑制剂分别被分类为I型和II型。在本研究中，遵循两种筛选方案来鉴定c-Yes激酶抑制剂。(i)基于结构的虚拟筛选（SBVS）和（ii）基于结构（SB）和基于药效团（PB）的串联筛选。在SBVS中，c-Yes激酶的结构是从同源建模和七个系综通过分子动力学（MD）模拟不同的活性位点支架获得的。对于SB-PB串联筛选，我们模拟了配体结合的活性和非活性构象。利用Src激酶家族和c-Yes激酶抑制剂的理化性质制备用于筛选的靶向聚焦文库。我们的筛选程序沿着对接显示SBVS和串联筛选中有520个可能的命中（分别为120和400）。从不同的计算方法确定的5000种化合物中，2410种使用激酶抑制试验进行了检查。共鉴定出266个化合物，占总鉴定量的5.32%。我们观察到，通过本方法在168种化合物中鉴定出14种化合物（12%），其显示>30%的抑制。其中，有三个化合物结构新颖、独特，表现出良好的抑制作用。此外，我们已经研究了这些化合物在DFG内和DFG外构象的结合，并报告了可能的类别（I型或II型）。因此，我们认为这些化合物可能是调节结直肠癌的新型药物先导。
c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors. (i) Structure-based virtual screening (SBVS) and (ii) Structure-based (SB) and Pharmacophore-based (PB) tandem screening. In SBVS, the c-Yes kinase structure was obtained from homology modeling and seven ensembles with different active site scaffolds through molecular dynamics (MD) simulations. For SB-PB tandem screening, we modeled ligand bound active and inactive conformations. Physicochemical properties of inhibitors of Src kinase family and c-Yes kinase were used to prepare target focused libraries for screenings. Our screening procedure along with docking showed 520 probable hits in SBVS and tandem screening (120 and 400, respectively). Out of 5000 compounds identified from different computational methods, 2410 were examined using kinase inhibition assays. It includes 266 compounds (5.32%) identified from our method. We observed that 14 compounds (12%) are identified by the present method out of 168 that showed>30% inhibition. Among them, three compounds are novel, unique, and showed good inhibition. Further, we have studied the binding of these compounds at the DFG-in and DFG-out conformations and reported the probable class (type I or type II). Hence, we suggest that these compounds could be novel drug leads for regulation of colorectal cancer.