Wu Yao, Gao Xin-Ying, Chen Xin-Hui, Zhang Shao-Long, Wang Wen-Juan, Sheng Xie-Huang, Chen De-Zhan
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Centre of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University Jinan 250014 P. R. China.
College of Physics and Electronics, Shandong Normal University Jinan 250014 P. R. China
RSC Adv. 2019 Mar 8;9(14):7757-7766. doi: 10.1039/c8ra09789e. eCollection 2019 Mar 6.
Understanding protein-ligand interactions is crucial to drug discovery and design. However, it would be extremely difficult for the proteins which only have one available apo structure but multiple binding sites. To address this constraint, a fragment-centric topographic mapping method (AlphaSpace software) was employed to map out concave interaction pockets at the assigned protein region. These pockets are used as complementary spaces to screen the known inhibitors for this specific binding site and to guide the molecular docking pose selection as well as protein-ligand interaction analysis. By mapping the shape of central cavity surface, we have tested the strategy against a multi-drug resistant transmembrane protein-ABCG2 to assist in generating a pharmacophore model for its inhibitors that is based on the structure of apo. Classical molecular simulation and accelerated molecular simulation are used to verify the accuracy of inhibitor screening and binding pose selection. Our study not only has gained insight for the development of novel specific ABCG2 inhibitors, but also has provided a general strategy in describing protein-ligand interactions.
理解蛋白质-配体相互作用对于药物发现和设计至关重要。然而，对于那些只有一个可用的无配体结构但有多个结合位点的蛋白质来说，这将极其困难。为了解决这一限制，采用了一种以片段为中心的拓扑映射方法（AlphaSpace软件）来绘制指定蛋白质区域的凹形相互作用口袋。这些口袋用作互补空间，以筛选针对该特定结合位点的已知抑制剂，并指导分子对接姿势选择以及蛋白质-配体相互作用分析。通过绘制中心腔表面的形状，我们针对一种多药耐药跨膜蛋白ABCG2测试了该策略，以协助基于无配体结构生成其抑制剂的药效团模型。使用经典分子模拟和加速分子模拟来验证抑制剂筛选和结合姿势选择的准确性。我们的研究不仅为新型特异性ABCG2抑制剂的开发提供了见解，还提供了一种描述蛋白质-配体相互作用的通用策略。
