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Structure-Based Discovery of Thiosemicarbazone Metalloproteinase Inhibitors for Hemorrhage Treatment in Snakebites
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-10-04 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00186
Francis B. Ferreira 1 , Thiago M. Pereira 1 , Dayane L. N. Souza 2 , Daiana S. Lopes 2 , Vitor Freitas 2 , Veridiana M. R. Ávila 2 , Arthur E. Kümmerle 1 , Carlos Mauricio R. Sant’Anna 1
Affiliation  

The venoms of snakes are composed by many toxins, which are responsible for various toxic effects including intense pain, bleeding disorders, and local tissue damage caused by hemorrhage and necrosis. The snake venom metalloproteinases (SVMPs) are proteolytic zinc-dependent enzymes acting in different hemostatic mechanisms. In this work, a structure-based molecular modeling strategy was used for the rational design, by means of a homology 3D model of an SVMP isolated from Bothrops pauloensis venom (BpMP-I), followed by synthesis and in vitro evaluation of new thiosemicarbazones as the first inhibitors of the B. pauloensis SVMP. Besides being effective for the SVMP inhibition, two molecules were shown to be effective also in vivo, inhibiting hemorrhage caused by the B. pauloensis whole venom. Docking studies on metalloproteinases from other snake species suggest that the thiosemicarbazones activity is not confined to BpMP-I, but seems to be a common feature of metzincins.

中文翻译:

基于结构的硫代氨基脲金属蛋白酶抑制剂在蛇咬伤中的出血治疗中的发现

蛇的毒液由许多毒素组成,这些毒素会引起各种毒性作用,包括剧烈的疼痛,出血性疾病以及由出血和坏死引起的局部组织损伤。蛇毒金属蛋白酶(SVMP)是蛋白水解锌依赖性酶,其作用于不同的止血机制。在这项工作中,基于结构的分子建模策略被用于合理设计,该方法是通过从鲍氏双胞胎毒液(BpMP-1)分离的SVMP的3D同源模型进行的,然后合成和体外评估新的硫代半脲酮类化合物B. pauloensis SVMP的首批抑制剂。除了有效抑制SVMP外,还显示了两个分子在体内也有效,抑制由芽孢杆菌全毒液引起的出血。对来自其他蛇种的金属蛋白酶的对接研究表明,硫半脲酮的活性不仅限于BpMP-1,而似乎是metzincins的共同特征。
更新日期:2017-10-04
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