Rejto P A, Verkhivker G M
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
Pac Symp Biocomput. 1998:362-73.
Ligand-protein docking simulations are employed to analyze the binding energy landscape of the pipecolinyl fragment that serves as a recognition core of the FK506 ligand in binding with the FKBP12 protein. This fragment acts as a molecular anchor that specifically binds within the protein active site in a unique binding mode, in harmony with the structure of the FK506-FKBP12 complex. Molecular anchors are characterized by a large stability gap, defined to be the free energy of a ligand bound in the native binding mode relative to the free energy of alternative binding modes. For ligands that share a common anchor fragment, a linear binding free energy relationship may be expected for hydrophobic substituents provided they do not abrogate the anchor binding mode. Changes in solvent-accessible surface area for these peripheral groups are used to rationalize the relative binding affinities of a series of FKBP12-ligand complexes which share the pipecolinyl anchor fragment. A series of benzene derivatives that bind to a mutant form of T4 lysozyme is also analyzed, and implications for structure-based drug design are discussed.
配体 - 蛋白质对接模拟用于分析哌啶基片段的结合能态势，该片段作为FK506配体与FKBP12蛋白结合时的识别核心。此片段充当分子锚，以独特的结合模式特异性结合于蛋白质活性位点内，与FK506 - FKBP12复合物的结构相协调。分子锚的特征是具有较大的稳定性差距，定义为以天然结合模式结合的配体的自由能相对于替代结合模式的自由能。对于共享共同锚定片段的配体，如果疏水取代基不破坏锚定结合模式，则可能预期存在线性结合自由能关系。这些外围基团的溶剂可及表面积变化用于合理化一系列共享哌啶基锚定片段的FKBP12 - 配体复合物的相对结合亲和力。还分析了一系列与T4溶菌酶突变形式结合的苯衍生物，并讨论了其对基于结构的药物设计的意义。
