Characterisation of hydrazides and hydrazine derivatives as novel aspartic protease inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 25; no. 5; pp. 673 - 678
• Main Authors: Ahmed, Waseem, Rani, Mubeen, Khan, Ishtiaq A., Iqbal, Asif, Khan, Khalid M., Haleem, M. A., Azim, M. Kamran
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.10.2010; Taylor & Francis
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - metabolism; Catalytic Domain; cathepsin D; Cathepsin D - antagonists & inhibitors; Cathepsin D - metabolism; Databases, Factual; Drug Evaluation, Preclinical; Humans; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - metabolism; malaria; Models, Molecular; Molecular Conformation; Osmolar Concentration; Phenylhydrazines - chemical synthesis; Phenylhydrazines - chemistry; Phenylhydrazines - metabolism; plasmepsin; Plasmodium falciparum - enzymology; protease inhibitors; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protein Interaction Domains and Motifs; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Virtual screening
• ISSN: 1475-6366; 1475-6374
• DOI: 10.3109/14756360903508430

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.