title: Differences between high- and low-affinity complexes of enzymes and nonenzymes.
abstract: Physical differences in small molecule binding between enzymes and nonenzymes were found through mining the protein-ligand database, Binding MOAD (Mother of All Databases). The data suggest that divergent approaches may be more productive for improving the affinity of ligands for the two classes of proteins. High-affinity ligands of enzymes are much larger than those with low affinity, indicating that the addition of complementary functional groups is likely to improve the affinity of an enzyme inhibitor. However, this process may not be as fruitful for ligands of nonenzymes. High- and low-affinity ligands of nonenzymes are nearly the same size, so modest modifications and isosteric replacement might be most productive. The inherent differences between enzymes and nonenzymes have significant ramifications for scoring functions and structure-based drug design. In particular, nonenzymes were found to have greater ligand efficiencies than enzymes. Ligand efficiencies are often used to indicate druggability of a target, and this finding supports the feasibility of nonenzymes as drug targets. The differences in ligand efficiencies do not appear to come from the ligands; instead, the pockets yield different amino acid compositions despite very similar distributions of amino acids in the overall protein sequences.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. carlsonh@umich.edu
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Nickolay A
authors.initials: NA
authors.lastname: Khazanov
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.forename: James B
authors.initials: JB
authors.lastname: Dunbar
authors.forename: Mark L
authors.initials: ML
authors.lastname: Benson
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes; D008024:Ligands; D011506:Proteins