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

Rejto PA, Verkhivker GM

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

Pac Symp Biocomput. 1998;:362-73.


Abstract

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.


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