Neves Bruno J, Braga Rodolpho C, Bezerra José C B, Cravo Pedro V L, Andrade Carolina H
LabMol - Laboratory for Drug Design and Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
LabMol - Laboratory for Drug Design and Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil; Instituto de Química, Universidade Federal de Goiás, Goiaânia, Brazil.
PLoS Negl Trop Dis. 2015 Jan 8;9(1):e3435. doi: 10.1371/journal.pntd.0003435. eCollection 2015 Jan.
Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.
在发展中国家，血吸虫病所致的发病率和死亡率是严重的公共卫生问题。由于吡喹酮是唯一用于治疗的药物，耐药风险令人担忧。在寻找新型杀血吸虫药物的过程中，我们对一个包含2114种蛋白质的数据集进行了基于靶点的化学基因组学筛选，以确定已获批准用于人类临床的、可能对曼氏血吸虫多个生活阶段有效的药物。这些蛋白质中的每一种都被视为潜在的药物靶点，其氨基酸序列用于查询三个数据库：治疗靶点数据库（TTD）、药物银行和STITCH。使用包括成对比对、功能区域保守状态和化学空间分析在内的多种方法组合，对预测的药物-靶点相互作用进行优化。为验证我们的策略，几种先前显示对血吸虫有活性的药物被正确预测，如氯硝西泮、金诺芬、硝苯地平和青蒿琥酯。我们还能够识别出115种尚未针对血吸虫进行实验测试且需要进一步评估的药物。一些例子是阿普林定、庆大霉素、克霉唑、丁苯那嗪、灰黄霉素和桂利嗪。总之，我们开发了一种系统且有针对性的计算机辅助方法，以提出可能值得测试和/或用作设计抗血吸虫新药先导化合物的已批准药物。
