title: Characterisation of hydrazides and hydrazine derivatives as novel aspartic protease inhibitors.
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 (IC(50) = 1-2.5 microM). 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.
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Waseem
authors.initials: W
authors.lastname: Ahmed
authors.forename: Mubeen
authors.initials: M
authors.lastname: Rani
authors.forename: Ishtiaq A
authors.initials: IA
authors.lastname: Khan
authors.forename: Asif
authors.initials: A
authors.lastname: Iqbal
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Khan
authors.forename: M A
authors.initials: MA
authors.lastname: Haleem
authors.forename: M Kamran
authors.initials: MK
authors.lastname: Azim
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009994:Osmolar Concentration; D010659:Phenylhydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D001559:Benzhydryl Compounds; D006834:Hydrazines; D010659:Phenylhydrazines; D011480:Protease Inhibitors; D015800:Protozoan Proteins; C032041:1,2-diphenylhydrazine; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II; C533922:CTSD protein, human; D002402:Cathepsin D