Molecular anchors with large stability gaps ensure linear binding free energy relationships for hydrophobic substituents.
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.
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
P A
PA
Rejto
G M
GM
Verkhivker
D000495:Allosteric Site; D017122:Bacteriophage T4 / Q000201:enzymology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D020104:Immunophilins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009113:Muramidase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D012984:Software; D016559:Tacrolimus / Q000737:chemistry* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D013816:Thermodynamics
D008024:Ligands; D009113:Muramidase; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus