de Souza Anacleto S, de Oliveira Marcelo T, Andricopulo Adriano D
Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Avenida João Dagnone 1100, São Carlos, SP, 13563-120, Brazil.
Instituto de Química de São Carlos, Universidade de São Paulo, Avenida Trabalhador são-carlense 400, São Carlos, SP, 13566-590, Brazil.
J Comput Aided Mol Des. 2017 Sep;31(9):801-816. doi: 10.1007/s10822-017-0039-0. Epub 2017 Aug 9.
Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0.82) from a series of non-covalent cruzain inhibitors represented mostly by oxadiazoles (lead compound, IC = 200 nM). Both models allowed us to map key intermolecular interactions in S1', S2 and S3 cruzain sub-sites (including halogen bond and C‒H/π). To probe the predictive capacity of obtained models, inhibitors available in the literature from different classes displaying a range of scaffolds were evaluate achieving mean absolute deviation of 0.33 and 0.51 for 2D and 3D models, respectively. CoMFA revealed an unexplored region where addition of bulky substituents to produce new compounds in the series could be beneficial to improve biological activity.
恰加斯病是一种由原生动物寄生虫克氏锥虫引起的被忽视的热带疾病。根据世界卫生组织的数据，全球有700万人感染，每年导致7000人死亡。现有的药物硝呋莫司和苯并咪唑，由于疗效低和毒性高而受到限制。作为一个经过验证的靶点，克鲁兹蛋白酶是治疗恰加斯病药物研发的一个主要方向。在此，我们描述了基于一系列主要由恶二唑（先导化合物，IC = 200 nM）代表的非共价克鲁兹蛋白酶抑制剂开发的二维定量构效关系（[公式：见原文] = 0.81）和基于三维定量构效关系的药效团（[公式：见原文] = 0.82）。这两个模型使我们能够描绘出克鲁兹蛋白酶S1'、S2和S3亚位点中的关键分子间相互作用（包括卤键和C-H/π）。为了探究所得模型的预测能力，对文献中不同类别、具有一系列骨架的抑制剂进行了评估，二维和三维模型的平均绝对偏差分别为0.33和0.51。比较分子场分析揭示了一个未被探索的区域，在该系列中添加庞大取代基以产生新化合物可能有利于提高生物活性。
