Send to

Choose Destination
Pac Symp Biocomput. 1998:362-73.

Molecular anchors with large stability gaps ensure linear binding free energy relationships for hydrophobic substituents.

Author information

Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.


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.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Pacific Sympsium On Biocomputing
Loading ...
Support Center