Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 20, Pages 6432-6441Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8006504
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Funding
- Beckman Young Investigator Award
- NSF [MCB-0546073]
- National Institutes of Health [HG003890]
- Molecular Biophysics Training Program [GM008270]
- Training Program in Bioinformatics [GM070449]
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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.
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