Leite Franco Henrique Andrade, Froes Thamires Quadros, da Silva Suellen Gonçalves, de Souza Evandro Italo Macêdo, Vital-Fujii Drielli Gomes, Trossini Gustavo Henrique Goulart, Pita Samuel Silva da Rocha, Castilho Marcelo Santos
Programa de Pós-graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Avenida Transnordestina, S/N, Novo Horizonte, Feira de Santana, Bahia CEP 44036-900, Brazil.
Laboratório de Cristalografia de Macromoléculas, Universidade Federal da Bahia, Salvador, Rua Barão do Jeremoabo, n° 147, Ondina, Salvador CEP 40170-115, Bahia, Brazil.
Eur J Med Chem. 2017 May 26;132:322-332. doi: 10.1016/j.ejmech.2017.03.043. Epub 2017 Mar 27.
Despite the fact that Leishmania ssp are pteridine auxotrophs, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major. On the other hand Pteridine Reductase 1 (PTR1) inhibitors proved to be lethal to the parasite. Aiming at identifying hits that lie outside the chemical space of known PTR1 inhibitors, pharmacophore models that differentiate true-binders from decoys and explain the structure-activity relationships of known inhibitors were employed to virtually screen the lead-like subset of ZINC database. This approach leads to the identification of Z80393 (IC = 32.31 ± 1.18 μM), whose inhibition mechanism was investigated by Thermal Shift Assays. This experimental result supports a competitive mechanism and was crucial to establish the docking search space as well as select the best pose, which was then investigated by molecular dynamics studies that corroborate the hit putative binding profile towards LmPTR1. The information gathered from such studies shall be useful to design more potent non-nucleoside LmPTR1 inhibitors.
尽管利什曼原虫属是蝶啶营养缺陷型，但二氢叶酸还原酶-胸苷酸合成酶（DHFR-TS）抑制剂对硕大利什曼原虫无效。另一方面，蝶啶还原酶1（PTR1）抑制剂已被证明对该寄生虫具有致死性。为了识别已知PTR1抑制剂化学空间之外的活性化合物，采用了能区分真正结合物与诱饵并解释已知抑制剂构效关系的药效团模型，对ZINC数据库中类先导化合物子集进行虚拟筛选。这种方法导致鉴定出Z80393（IC = 32.31 ± 1.18 μM），通过热位移分析研究了其抑制机制。该实验结果支持一种竞争机制，对于建立对接搜索空间以及选择最佳构象至关重要，随后通过分子动力学研究对其进行了研究，这些研究证实了该活性化合物对硕大利什曼原虫PTR1的假定结合模式。从这些研究中收集到的信息将有助于设计更有效的非核苷类硕大利什曼原虫PTR1抑制剂。
