Premium
Insight into Selectivity of Peptidomimetic Inhibitors with Modified Statine Core for Plasmepsin II of Plasmodium falciparum over Human Cathepsin D
Author(s) -
Dali Brice,
Keita Melalie,
Megnassan Eugene,
Frecer Vladimir,
Miertus Stanislav
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01276.x
Subject(s) - peptidomimetic , plasmodium falciparum , pharmacophore , chemistry , biochemistry , protease , enzyme , stereochemistry , biology , peptide , malaria , immunology
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 ( h CatD). h CatD is a protein digestion enzyme and signaling molecule involved in a variety of physiological processes; therefore, inhibition of h CatD by PlmII inhibitors may lead to pathophysiological conditions. In this study, binding of PlmII inhibitors has been modeled using the crystal structures of pf PlmII and h CatD complexes to gain insight into structural requirements underlying the target selectivity. A series of 26 inhibitors were modeled in the binding clefts of the pf PlmII and h CatD 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 P 2 and P 3′ 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 n m and selectivity index (S.I.) = > 1200.