Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries
Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries
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DOI：
10.1021/jm050701c
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发表时间：
2006-04-20
影响因子：
7.3
通讯作者：
Toney, MD
中科院分区：
文献类型：
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作者：
Dixon, SM;Li, P;Toney, MD
单头单化合物组合化学以及基于荧光标记酶的高通量筛选允许鉴定人类丝氨酸消旋酶（hSR）的慢结合抑制剂。合成了一个拓扑分离的编码树脂珠肽库，并分离、鉴定和重新合成了几个hsr结合化合物，以进行进一步的动力学研究。其中，几种对hSR表现出中等效价（高微摩尔K(l)s）的抑制作用。确定了一个清晰的结构基序，由3-苯基丙酸和组氨酸组成。重要的是，所鉴定的抑制剂与天然底物l -丝氨酸没有结构相似性。对所选抑制剂性质的详细动力学分析表明，这里使用的筛选方案选择性地识别慢结合抑制剂。它们为未来分离更有效的配体提供了药效团，这些配体可能有助于探索和理解hSR的生物学作用。
One-bead one-compound combinatorial chemistry together with a high-throughput screen based on fluorescently labeled enzyme allowed the identification of slow binding inhibitors of human serine racemase (hSR). A peptide library of topographically segregated encoded resin beads was synthesized, and several hSR-binding compounds were isolated, identified, and resynthesized for further kinetic study. Of these, several showed inhibitory effects with moderate potency (high micromolar K(l)s) toward hSR. A clear structural motif was identified consisting of 3-phenylpropionic acid and histidine moieties. Importantly, the inhibitors identified showed no structural similarities to the natural substrate, L-serine. Detailed kinetic analyses of the properties of selected inhibitors show that the screening protocol used here selectively identifies slow binding inhibitors. They provide a pharmacophore for the future isolation of more potent ligands that may prove useful in probing and understanding the biological role of hSR.