University of Cape Town, Department of Chemistry, Rondebosch, 7701, South Africa.
University of Cape Town, Division of Pharmacology, Department of Medicine, Observatory, 7925, South Africa.
Sci Rep. 2020 Feb 25;10(1):3374. doi: 10.1038/s41598-020-60221-0.
Malaria remains a major public health problem. With the loss of antimalarials to resistance, the malaria burden will likely continue for decades. New antimalarial scaffolds are crucial to avoid cross-resistance. Here, we present the first structure based virtual screening using the β-haematin crystal as a target for new inhibitor scaffolds by applying a docking method. The ZINC15 database was searched for compounds with high binding affinity with the surface of the β-haematin crystal using the PyRx Virtual Screening Tool. Top-ranked compounds predicted to interact with β-haematin were submitted to a second screen applying in silico toxicity and drug-likeness predictions using Osiris DataWarrior. Fifteen compounds were purchased for experimental testing. An NP-40 mediated β-haematin inhibition assay and parasite growth inhibition activity assay were performed. The benzoxazole moiety was found to be a promising scaffold for further development, showing intraparasitic haemozoin inhibition using a cellular haem fractionation assay causing a decrease in haemozoin in a dose dependent manner with a corresponding increase in exchangeable haem. A β-haematin inhibition hit rate of 73% was found, a large enrichment over random screening, demonstrating that virtual screening can be a useful and cost-effective approach in the search for new haemozoin inhibiting antimalarials.
疟疾仍然是一个主要的公共卫生问题。随着抗疟药物因耐药性而失效，疟疾负担可能会持续数十年。新的抗疟药物支架对于避免交叉耐药性至关重要。在这里，我们首次基于β-血红素晶体作为新抑制剂支架的目标进行了基于结构的虚拟筛选，应用对接方法。使用 PyRx Virtual Screening Tool，在 ZINC15 数据库中搜索与β-血红素晶体表面具有高结合亲和力的化合物。预测与β-血红素相互作用的顶级化合物使用 Osiris DataWarrior 进行了第二重筛选，应用了计算机毒性和药物相似性预测。购买了 15 种化合物进行实验测试。进行了 NP-40 介导的β-血红素抑制测定和寄生虫生长抑制活性测定。发现苯并恶唑部分是进一步开发的有前途的支架，使用细胞血红素分馏测定显示在寄生虫内血红素抑制，导致血红素抑制呈剂量依赖性，相应的可交换血红素增加。发现β-血红素抑制的命中率为 73%，远远超过随机筛选，表明虚拟筛选可以成为寻找新的血红素抑制抗疟药物的一种有用且具有成本效益的方法。
