title: Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
abstract: A high-resolution crystallographic structure determination of a protein-ligand complex is generally accepted as the 'gold standard' for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein-ligand interactions and emphasize the difficulties in predicting affinity from structure.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tziridis
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: Piotr
authors.initials: P
authors.lastname: Neumann
authors.forename: Petr
authors.initials: P
authors.lastname: Kolenko
authors.forename: Anja
authors.initials: A
authors.lastname: Menzel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bräuer
authors.forename: Christian
authors.initials: C
authors.lastname: Ursel
authors.forename: Peter
authors.initials: P
authors.lastname: Steinmetzer
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Milton T
authors.initials: MT
authors.lastname: Stubbs
mesh_terms: D055808:Drug Discovery; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa