Sodero Ana Carolina R, Dos Santos Ana Carolina G O, Mello Juliana F R E, DE Jesus Jéssica B, DE Souza Alessandra M T, Rodrigues Maria Isabel C, DE Simone Salvatore G, Rodrigues Carlos R, DE Matos Guedes Herbert L
Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
Centro de Desenvolvimento Tecnológico em Saúde (CDTS)/Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN),21045-900 Rio de Janeiro, RJ,Brazil.
Parasitology. 2017 Apr;144(4):536-545. doi: 10.1017/S0031182016002237. Epub 2016 Dec 29.
Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.
利什曼病是由利什曼原虫属的寄生虫引起的疾病，通过感染的白蛉亚科昆虫叮咬传播给人类。目前的药物治疗显示出高毒性和严重的不良反应。最近，在亚马逊利什曼原虫中鉴定出两种寡肽酶（OPB），即寡肽酶B（OPB）和寡肽酶B2（OPB2）。这些OPB可能是理想的靶点，因为这两种酶在寄生虫的整个生命周期中均有表达，而在人类中未发现。这项工作旨在从亚马逊利什曼原虫中鉴定出可能的OPB和OPB2双重抑制剂。通过比较建模构建了这两种酶的三维结构，并用于通过DOCK Blaster服务器对ZINC数据库进行虚拟筛选。这是首次将来自亚马逊利什曼原虫的OPB模型用于虚拟筛选方法。每种酶鉴定出400种化合物作为可能的抑制剂。得分最高的化合物通过AutoDock程序进行优化。最佳结果表明，化合物与重要残基相互作用，如Tyr490、Glu612和Arg655（OPB编号）。当进行计算机辅助药物代谢动力学（ADMET）分析时，鉴定出的化合物显示出比抑肽酶和目前用于治疗利什曼病的药物更好的结果。可以对这些化合物进行研究，以找到来自亚马逊利什曼原虫的OPB和OPB2双重抑制剂。
