Abstract
Virtual screening of an in-house virtual library of synthetic compounds using FlexX, followed by enzyme inhibition, identified hydrazide and hydrazine derivatives as novel aspartic protease inhibitors. These compounds inhibited human cathepsin D and Plasmodium falciparum plasmepsin-II with low micromolar concentrations (IC50 = 1-2.5 μM). Modelling studies with plasmepsin-II predicted binding of ligands at the centre of the extended substrate-binding cleft, where hydrazide/hydrazine parts of the inhibitors acted as the transition state mimic by forming electrostatic interactions with catalytic aspartates.
Acknowledgements
We are thankful to Dr Daniel E. Goldberg (Howard Hughes Medical Institute, Washington University, School of Medicine, St Louis, Missouri, USA) for providing purified P. falciparum plasmepsin-II, and Dr M. Iqbal Choudhary, University of Karachi, Karachi, Pakistan for valuable suggestions.
Declaration of interest
The author reports no conflicts of interest. The authors alone are responsible for the content and writing of the paper.