Receptor preparation
The co-crystallized structure of human FXR with GW4064 analogue (PDB code: 3FXV, resolution: 番茄焖牛腩2.26 Å) was lected for docking study. The structures were prepared using the “Protein Preparation Wizard” module in Maestro (ref.1). The protein was prepared by adding missing hydrogen atoms, assigning ligand bond orders, determining ligand protonation state, removing waters, optimizing hydrogen bond network, and performing a restrained minimization, etc. Docking grid files were then generated using the “Receptor Grid Generation” module at their default ttings.
Ligand preparation
Compounds were prepared with LigPrep (ref. 2) to generate 3D structures including all possible stereoisomers and tautomers. Epik (ref. 3) was chon to generate all possible protonation states of the compounds at a pH from 5.0 to 9.0. OPLS_2005 was adopted as force field. The remaining parameters were ud at their default values. The conformation of each structure was sampled using macromodel (ref. 4) with “conformational CSearch” pr
otocol. 风的反义词The top 10 reprentative conformations were obtained after a clustering analysis by RMSD.
Preci docking by Glide职场资讯
The Glide (ref. 5) software can突兀的反义词 perform high accuracy docking. During the grid generation, six hydrogen bond constraints were t up including His451 (HBA), Tyr365 (HBD), Tyr373 (HBD), Ser336 (HBA), Arg335 (HBD) and His298 (HBA). At least one hydrogen bond must match was t up for docking. All the docking calculations were performed by the Standard Precision mode去斑去痘印. The predicted binding modes were chon by combining with the docking score and the protein ligand interaction pattern.
蛋白准备：
选择人类FXR蛋白与GW4064类似物的复合物的晶体结构（PDB代码: 3FXV桂花园小学, 分辨率: 2.26 Å）作为对接的模板。复合物的结构采用Maestro的“Protein Preparation Wizard”模块进行准备。通过加氢，分配键级，去水，优化氢键网络，带有限制的能量优化等将蛋白处理好。对接使用的格点文件通过“Receptor Grid Generation”模块采用默认设置产生。
配体准备：
采用LigPrep对化合物进行三维结构的转换，包括产生所有可能的立体异构和互变异构体。其中选择菠菜拌花生Epik方法来产生化合物在pH从 5.0到9.0范围内所有可能的质子化状态。采用液位浮球阀OPLS_2005力场。其他的设置采用默认的参数。之后采用Macromodel 中的“conformational CSearch”模块对每个结构进行构象的采样，然后通过对RMSD进行聚类分析的方法挑出前10个最有代表性的构象。
Glide对接：
Glide是一款能够进行小分子与受体之间精确对接的软件。在格点文件产生的过程中设置了6个氢键的限制包括His451 (HBA)， Tyr365 (HBD)， Tyr373 (HBD)， Ser336 (HBA)，Arg335 (HBD) 和 His298 (HBA)。在对接过程中要求至少满足要与其中一个残基形成氢键。采用Glide的标准精度模式进行所有的对接计算。综合考虑对接打分和配体与受体之间的相互作用模式来挑选最有可能的结合模式。
References:
Ref. 1: Maestro, version 9.9, Schrödinger, LLC, New York, NY, 2014.
Ref. 2: LigPrep, version 3.2, Schrödinger, LLC, New York, NY, 2014.
Ref. 3: Epik, version 3.0, Schrödinger, LLC, New York, NY, 2014.
Ref. 4: MacroModel, version 10.6, Schrödinger, LLC, New York, NY, 2014.
Ref. 5: Glide, version 6.5, Schrödinger, LLC, New York, NY, 2014.
