Griffith Institute for Drug Discovery, Griffith University, Nathan 4111, Australia.
Institut für pharmazeutische und medizinische Chemie, Heinrich-Heine Universität, Dusseldorf 40225, Germany.
ACS Infect Dis. 2022 Jan 14;8(1):106-117. doi: 10.1021/acsinfecdis.1c00355. Epub 2022 Jan 5.
Malaria, caused by parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets. Here, we describe quantitative structure-activity relationship models to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors. The models incorporate in vitro activity data for 385 compounds containing a hydroxamic acid and were subject to internal and external validation. When used to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial activity, model (external accuracy 91%) identified three hits that were subsequently verified as having potent in vitro activity against parasites (IC = 6, 71, and 84 nM), with 8 to 51-fold selectivity for versus human cells.
疟疾是由寄生虫引起的，每年导致超过 40 万人死亡。由于寄生虫对现有抗疟药物的耐药性不断增加，因此需要具有新作用模式的新型药物。组蛋白去乙酰化酶（HDACs）是一种表观遗传调节酶，可催化翻译后蛋白质去乙酰化，是有前途的疟疾药物靶点。在这里，我们描述了基于定量构效关系的模型，以预测基于羟肟酸的 HDAC 抑制剂的抗疟活性。这些模型纳入了包含羟肟酸的 385 种化合物的体外活性数据，并经过内部和外部验证。当用于筛选 22 种新型基于羟肟酸的 HDAC 抑制剂的抗疟活性时，模型（外部准确性为 91%）鉴定出三种具有针对疟原虫（IC = 6、71 和 84 nM）的有效体外活性的化合物，对人类细胞具有 8 至 51 倍的选择性。
