Malonate-based inhibitors of mammalian serine racemase: kinetic characterization and structure-based computational study.
Malonate-based inhibitors of mammalian serine racemase: kinetic characterization and structure-based computational study.
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DOI：
10.1016/j.ejmech.2014.10.043
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发表时间：
2015-01
影响因子：
6.7
通讯作者：
Barbora Vorlová;D. Nachtigallová;Jana Jirásková-Vaníčková;H. Ajani;P. Jansa;J. Řezáč;J. Fanfrlík;M. Otyepka;P. Hobza;J. Konvalinka;M. Lepšík
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文献类型：
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作者：
Barbora Vorlová;D. Nachtigallová;Jana Jirásková-Vaníčková;H. Ajani;P. Jansa;J. Řezáč;J. Fanfrlík;M. Otyepka;P. Hobza;J. Konvalinka;M. Lepšík
NMDA 受体过度激活与多种神经病理学病症有关，包括脑缺血、神经退行性疾病和癫痫。 d-丝氨酸（一种 NMDA 受体共激动剂）在体内由 5'-磷酸吡哆醛 (PLP) 依赖性酶丝氨酸消旋酶催化产生。对该酶的特异性抑制已被认为是治疗由 NMDA 受体功能障碍引起的神经系统疾病的一种有前景的策略。在此，我们介绍了一系列基于丙二酸的小鼠丝氨酸消旋酶 (mSR) 抑制剂的合成和活性分析。这些化合物的 IC50 值范围从 2,2-双（羟甲基）丙二酸的 40 ± 11 mM 到 2,2-二氯丙二酸的 57 ± 1 μM，这是迄今为止已知的最有效的竞争性 mSR 抑制剂。利用Glide对接、水合WaterMap分析和基于hSR/丙二酸复合物的X射线结构的量子力学计算，解释了人类直系同源物(hSR)中整个系列的构效关系。用三个热力学有利的水分子对接 hSR 活性位点能够定性地区分良好和弱的抑制剂。使用先进的 PM6-D3H4X/COSMO 基于半经验量子力学的评分进一步提高了排名，该评分区分了 IC50 优于/差于 2 mM 的化合物。因此，我们不仅发现了一种新的有效的 hSR 抑制剂，而且还制定了一种计算机辅助方案来合理化结合亲和力，从而有助于寻找更有效的 SR 抑制剂。新型、有效的 hSR 抑制剂可能代表有趣的研究工具以及治疗与 NMDA 受体过度激活相关疾病的候选药物。
Overactivation of NMDA receptors has been implicated in various neuropathological conditions, including brain ischaemia, neurodegenerative disorders and epilepsy. Production ofd-serine, an NMDA receptor co-agonist, froml-serine is catalyzedin vivoby the pyridoxal-5′-phosphate (PLP)-dependent enzyme serine racemase. Specific inhibition of this enzyme has been proposed as a promising strategy for treatment of neurological conditions caused by NMDA receptor dysfunction.Here we present the synthesis and activity analysis of a series of malonate-based inhibitors of mouse serine racemase (mSR). The compounds possessed IC50values ranging from 40 ± 11 mM for 2,2-bis(hydroxymethyl)malonate down to 57 ± 1 μM for 2,2-dichloromalonate, the most effective competitive mSR inhibitor known to date. The structure–activity relationship of the whole series in the human orthologue (hSR) was interpreted using Glide docking, WaterMap analysis of hydration and quantum mechanical calculations based on the X-ray structure of the hSR/malonate complex. Docking into the hSR active site with three thermodynamically favourable water molecules was able to discern qualitatively between good and weak inhibitors. Further improvement in ranking was obtained using advanced PM6-D3H4X/COSMO semiempirical quantum mechanics-based scoring which distinguished between the compounds with IC50better/worse than 2 mM. We have thus not only found a new potent hSR inhibitor but also worked out a computer-assisted protocol to rationalize the binding affinity which will thus aid in search for more effective SR inhibitors. Novel, potent hSR inhibitors may represent interesting research tools as well as drug candidates for treatment of diseases associated with NMDA receptor overactivation.