Differences between High- and Low-Affinity Complexes of Enzymes and Nonenzymes. Export

@article{citeulike:3374934, 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.}, author = {Carlson, Heather A. and Smith, Richard D. and Khazanov, Nickolay A. and Kirchhoff, Paul D. and Dunbar, James B. and Benson, Mark L.}, citeulike-article-id = {3374934}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/jm8006504}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/jm8006504}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18826206}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18826206}, day = {1}, doi = {10.1021/jm8006504}, issn = {1520-4804}, journal = {Journal of medicinal chemistry}, keywords = {affinity, enzyme, ligand, moad, p1, p2, protein}, month = {October}, pages = {6432--6441}, posted-at = {2009-01-21 20:43:54}, priority = {0}, title = {Differences between High- and Low-Affinity Complexes of Enzymes and Nonenzymes.}, url = {http://dx.doi.org/10.1021/jm8006504}, volume = {51}, year = {2008} }

TY - JOUR ID - citeulike:3374934 L3 - citeulike-article-id:3374934 N2 - 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. JF - Journal of medicinal chemistry SN - 1520-4804 EP - 6441 TI - Differences between High- and Low-Affinity Complexes of Enzymes and Nonenzymes. VL - 51 SP - 6432 KW - affinity KW - enzyme KW - ligand KW - moad KW - p1 KW - p2 KW - protein AU - Carlson, Heather AU - Smith, Richard AU - Khazanov, Nickolay AU - Kirchhoff, Paul AU - Dunbar, James AU - Benson, Mark PY - 2008/10/01/ UR - http://dx.doi.org/10.1021/jm8006504 ER -