Differences between high- and low-affinity complexes of enzymes and nonenzymes.
Differences between high- and low-affinity complexes of enzymes and nonenzymes.
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DOI：
10.1021/jm8006504
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发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Benson ML
中科院分区：
文献类型：
--
作者：
Carlson HA;Smith RD;Khazanov NA;Kirchhoff PD;Dunbar JB Jr;Benson ML
通过挖掘蛋白质-配体数据库Binding MOAD（Mother of All Databases），发现酶和非酶之间小分子结合的物理差异。这些数据表明，不同的方法可能更有效地提高两类蛋白质的配体的亲和力。酶的高亲和力配体比低亲和力的配体大得多，表明添加互补官能团可能会提高酶抑制剂的亲和力。然而，该过程对于非酶的配体可能不那么富有成效。非酶的高亲和力和低亲和力配体的大小几乎相同，因此适度的修饰和电子等排置换可能是最有效的。酶和非酶之间的固有差异对评分功能和基于结构的药物设计具有重要影响。特别地，发现非酶具有比酶更大的配体效率。配体效率通常用于指示靶点的可药物化性，这一发现支持非酶作为药物靶点的可行性。配体效率的差异似乎不是来自配体;相反，口袋产生不同的氨基酸组成，尽管氨基酸在整个蛋白质序列中的分布非常相似。
Physical differences in small molecule binding between enzymes and non-enzymes 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 non-enzymes. High- and low-affinity ligands of non-enzymes are nearly the same size, so modest modifications and isosteric replacement might be most productive. The inherent differences between enzymes and non-enzymes have significant ramifications for scoring functions and structure-based drug design. In particular, non-enzymes 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 non-enzymes 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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