Expanding the chemical space of human serine racemase inhibitors
Expanding the chemical space of human serine racemase inhibitors
复制标题
DOI：
10.1016/j.bmcl.2015.07.081
复制
发表时间：
2015-10-01
影响因子：
2.7
通讯作者：
Mozzarelli, Andrea
中科院分区：
文献类型：
--
作者：
Dellafiora, Luca;Marchetti, Marialaura;Mozzarelli, Andrea
丝氨酸消旋酶是中枢神经系统中负责 D-丝氨酸合成的酶，已被确定为治疗 N-甲基-D-天冬氨酸受体相关病理的潜在治疗靶点。对该酶的特异性抑制剂的搜索表明，丝氨酸消旋酶是一个困难的靶标，目前确定的最佳抑制剂是 2,2-二氯丙二酸，其 K-i 为 19 mu M。为了扩大命中化合物的化学空间，我们应用 FLAP 软件对过滤的 ZINC 库进行了基于计算机结构的筛选活动。鉴定出的命中物与 GOLD 对接，并用 HINT 重新评分，并在重组人丝氨酸消旋酶上对最有前途的分子进行实验评估。两种抑制剂的化学结构与迄今为止描述的抑制剂完全无关，其 K-i 值约为 1.5 mM。 (C) 2015 Elsevier Ltd. 保留所有权利。
Serine racemase, the enzyme responsible for D-serine synthesis in the central nervous system, has been identified as a potential therapeutic target to treat N-methyl-D-aspartate receptors-related pathologies. The search for specific inhibitors of the enzyme has revealed that serine racemase is a difficult target, with the best inhibitor currently identified, 2,2-dichloromalonate, showing a K-i of 19 mu M. In order to expand the chemical space of hit compounds, we have performed an in silico structure-based screening campaign on a filtered ZINC library applying the FLAP software. The identified hits were docked with GOLD and re-scored with HINT, and the most promising molecules experimentally evaluated on recombinant human serine racemase. Two inhibitors, with chemical structures totally unrelated to inhibitors described so far showed K-i values of about 1.5 mM. (C) 2015 Elsevier Ltd. All rights reserved.