Insight into Selectivity of Peptidomimetic Inhibitors with Modified Statine Core for Plasmepsin II of Plasmodium falciparum over Human Cathepsin D

Plasmepsin II (PlmII), an aspartic protease expressed in the food vacuole of Plasmodium falciparum (pf), cleaves the hemoglobin of the host during the erythrocytic stage of the parasite life cycle. Various peptidomimetic inhibitors of PlmII reported so far discriminate poorly between the drug target and aspartic proteases of the host organism, e.g., human cathepsin D (hCatD). hCatD is a protein digestion enzyme and signaling molecule involved in a variety of physiological processes; therefore, inhibition of hCatD by PlmII inhibitors may lead to pathophysiological conditions. In this study, binding of PlmII inhibitors has been modeled using the crystal structures of pfPlmII and hCatD complexes to gain insight into structural requirements underlying the target selectivity. A series of 26 inhibitors were modeled in the binding clefts of the pfPlmII and hCatD to establish QSAR models of the protease inhibition. In addition, 3D‐QSAR pharmacophore models were generated for each enzyme. It was concluded that the contributions of the P2 and P3′ residues to the inhibitor’s binding affinity are responsible for the target selectivity. Based on these findings, new inhibitor candidates were designed with predicted inhibition constants reaching 0.2 nm and selectivity index (S.I.) =  > 1200.