De Novo Design, Synthesis, and In Vitro Evaluation of a New Class of Nonpeptidic Inhibitors of the Malarial Enzyme Plasmepsin II

Pocket change: A new family of plasmepsin II inhibitors (see scheme) was developed by taking advantage of the putative flexibility of plasmepsin II and employment of a structure-based de novo design approach based on molecular recognition principles. A newly accessible hydrophobic pocket unlocked by conformational changes that occur upon bonding of adequate inhibitors was proposed. This site was targeted by nonpeptidic plasmepsin II inhibitors, which displayed single-digit micromolar activity in an enzyme assay.