Fighting Malaria: Structure-Guided Discovery of Nonpeptidomimetic Plasmepsin Inhibitors

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• 作者：Anja P. Huizing ; Milon Mondal ; Anna K. H. Hirsch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：58
• 期：13
• 页码：5151-5163
• 全文大小：793K
• ISSN：1520-4804

文摘

Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I鈥揑V developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I鈥揑V and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles.