Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 9, Pages 3011-3015Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.02.060
Keywords
virtual screening; protease inhibitors; cathepsin D; plasmepsin; acridines
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We have identified acridinyl derivatives as potent aspartic protease inhibitors by virtual screening of in-house library of synthetic compounds. Enzyme inhibition experiments showed that both compounds inhibit human cathepsin D and Plasmodium falciparum plasmepsin-II in nanomolar ranges. The IC50 values against cathepsin D and plasmepsin-II of compound-Nar103 were found to be 9.0 +/- 2.0 and 4.0 +/- 1.0 nM and of compound-Nar110 were 0.5 +/- 0.05 and 0.13 +/- 0.03 nM, respectively. Ligand docking predicted the binding of acridinyl derivatives at the substrate-binding cleft, where hydrazide part of the inhibitors interact with the S1-S1' subsite residues including catalytic aspartates. The phenyl ring and acridinyl moiety of the inhibitors were predicted to interact with S2/S3 and S2'/S3' subsite residues. (C) 2008 Elsevier Ltd. All rights reserved.
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