<i>In Silico</i> Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of <i>Schistosoma mansoni</i>

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.血吸虫病所引发的发病与死亡，是发展中国家亟待解决的严重公共卫生问题。由于吡喹酮是目前唯一获批的临床治疗用药，耐药性风险已成为学界关注的潜在隐患。为发掘新型抗血吸虫药物，我们针对包含2114种蛋白质的数据集开展基于靶点的化学基因组学筛选，旨在鉴定出已获批用于人类临床使用、且可能对曼氏血吸虫（Schistosoma mansoni）多个生活史阶段发挥活性的药物。我们将数据集内的每种蛋白质均视为潜在药物靶点，并以其氨基酸序列作为检索依据，分别对治疗靶点数据库（Therapeutic Target Database, TTD）、DrugBank数据库以及STITCH数据库进行检索。我们结合两两序列比对、功能区域保守性分析以及化学空间分析等多种方法，对预测得到的药物-靶点相互作用进行优化修正。为验证本研究策略的可靠性，我们成功预测出数种此前已被证实对血吸虫具有活性的药物，包括氯硝西泮、金诺芬、硝苯地平以及青蒿琥酯。本研究同时筛选出115种尚未经血吸虫感染实验验证的药物，有待开展进一步评估，其中代表性药物包括阿普林定、庆大霉素、克霉唑、丁苯那嗪、灰黄霉素以及桂利嗪。综上，本研究开发了一套系统性且聚焦性的计算机辅助研究方法，可筛选出值得开展实验验证、或可作为新型抗血吸虫药物研发先导化合物的已获批临床用药。