Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
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DOI：
10.1371/journal.pone.0060955
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Minoprio P
中科院分区：
文献类型：
--
作者：
Berneman A;Montout L;Goyard S;Chamond N;Cosson A;d'Archivio S;Gouault N;Uriac P;Blondel A;Minoprio P
恰加斯病是由克氏锥虫引起的，克氏锥虫是一种原生动物，通过吸血昆虫、输血或先天性传播给人类。以前的研究使我们发现了一种寄生虫脯氨酸消旋酶（TcPRAC），并确定其作为设计新的化疗药物（包括其慢性形式）的有效性。已知的脯氨酸消旋酶抑制剂2-吡咯羧酸（PYC）是水不溶性的。我们合成了可溶性吡唑衍生物，但它们被证明是弱的或无活性的TcPRAC抑制剂。TcPRAC催化位点太小，并且当与PYC结合时受到限制，从而不能通过虚拟筛选有效地搜索新的抑制剂。通过计算一个过渡路径，我们开发的方法，建立了49个中间构象之间的开放的酶结构和封闭的配体之一。更广泛的化合物可以在计算机中对接在部分开放的中间活性位点模型中。针对已知的底物选择了四种模型，弱抑制剂可以停靠在其中，并用于筛选化学文库。两种已鉴定的可溶性化合物（E）-4-氧戊-2-烯酸（OxoPA）及其衍生物（E）-5-溴-4-氧戊-2-烯酸（Br-OxoPA）是不可逆的竞争性抑制剂，对TcPRAC的活性比PYC更强。我们在这里表明，增加剂量的OxoPA和Br-OxoPA阻碍T。哺乳动物宿主细胞中的Cruzi细胞内分化和命运。我们的数据证实，通过它们的结合模式，这些分子是有趣的和有前途的先导化合物，用于开发针对活性脯氨酸消旋酶发挥重要作用的疾病的化学疗法。
Chagas’ disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.
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影响因子：
2.8
作者：
FISCHER, S;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
12
作者：
Garraud, O;Andreu, G;Lefrere, J-J
通讯作者：
Lefrere, J-J
DOI：
10.1080/14756360412331280536
发表时间：
2004-12-01
影响因子：
5.6
作者：
Gouault, N;Pinel, B;David, M
通讯作者：
David, M
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1590/s0074-02762009000800001
发表时间：
2009-12-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Coutinho, Leticia;Ferreira, Marcelo Alves;Soeiro, Maria de Nazaré Correia
通讯作者：
Soeiro, Maria de Nazaré Correia