Shen Lingling, Huang Hongwei, Makriyannis Alexandros, Fisher Luke S
Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA.
Curr Comput Aided Drug Des. 2012 Dec 1;8(4):330-4. doi: 10.2174/157340912803519615.
3D pharmacophore modeling is an important computational methodology for ligand-enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH.
3D药效团建模是药物发现中配体-酶结合相互作用的一种重要计算方法。更具体地说，源自多种配体的一致性药效团模型是计算模型预测能力的关键决定因素，基于此来设计新型配体。在这项工作中，通过合并基于四类共价脂肪酸酰胺水解酶（FAAH）配体的重要药效团特征，然后整合从晶体结构衍生出的排阻体积球，我们首次创建了一个综合的FAAH药效团模型来描述配体-酶结合相互作用。这个新的综合FAAH药效团模型可以正确预测共价配体的结合模式，这与构效关系（SAR）数据相关。该研究有望为新型共价配体-FAAH结合相互作用提供见解，并促进针对FAAH的共价配体的设计。
