Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors.
Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors.
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DOI：
10.1371/journal.pone.0031610
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Borri Voltattorni C
中科院分区：
文献类型：
--
作者：
Daidone F;Montioli R;Paiardini A;Cellini B;Macchiarulo A;Giardina G;Bossa F;Borri Voltattorni C
多巴胺脱羧酶（DDC）是一种负责多巴胺和5-羟色胺生物合成的吡哆醛5′-磷酸（PLP）酶，与帕金森病（PD）有关。PD是一种神经退行性疾病，主要是由于中脑中产生多巴胺的细胞的进行性损失。左旋多巴与外周DDC抑制剂（卡比多巴或苄丝肼）联合给药是PD最有效的对症治疗。虽然卡比多巴和三羟基苄肼（苄丝肼的体内水解产物）都是强大的不可逆DDC抑制剂，但它们不是选择性的，因为它们不可逆地结合游离PLP和PLP酶，从而诱导各种副作用。因此，本研究的主要目标是（a）使用虚拟筛选来鉴定潜在的人类DDC抑制剂和（B）通过实验测试所选分子的“体外”活性来评估我们的虚拟筛选（VS）方案的可靠性。从DDC-carbidopa复合物的晶体结构出发，开发了一种新的结合药效团搜索和分子对接的VS方案。通过过滤公共ZINC数据库获得的15种选定化合物的分析，产生了两种与人DDC的活性位点结合的分子，并表现为Ki值≥10 µM的竞争性抑制剂。通过对后者化合物进行计算机相似性搜索，然后使用最具活性的化合物的核心进行子结构搜索，我们鉴定了几种人DDC的竞争性抑制剂，其Ki值在低微摩尔范围内，不能结合游离PLP，并且预测不会穿过血脑屏障。Ki值为500 nM的最有效抑制剂代表了一种新的先导化合物，靶向人DDC，这可能是开发新DDC抑制剂的先导化合物优化的基础。据我们所知，在DDC抑制剂的发现领域还没有类似的方法报道。
Dopa decarboxylase (DDC), a pyridoxal 5′-phosphate (PLP) enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD). PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide) is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide) are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a) to use virtual screening to identify potential human DDC inhibitors and (b) to evaluate the reliability of our virtual-screening (VS) protocol by experimentally testing the “in vitro” activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with Ki values ≥10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with Ki values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a Ki value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery.
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DOI：
10.1042/cs0560089
发表时间：
1979-01-01
期刊：
CLINICAL SCIENCE AND MOLECULAR MEDICINE
影响因子：
--
作者：
BENDER, DA;EARL, CJ;LEES, AJ
通讯作者：
LEES, AJ
DOI：
10.1038/nsb1101-963
发表时间：
2001-11-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Burkhard, P;Dominici, P;Malashkevich, VN
通讯作者：
Malashkevich, VN
影响因子：
2.9
作者：
CHARTERIS, A;JOHN, R
通讯作者：
JOHN, R
影响因子：
5.8
作者：
BENDER, DA
通讯作者：
BENDER, DA
影响因子：
7.3
作者：
Bissantz, C;Folkers, G;Rognan, D
通讯作者：
Rognan, D