title: Identification of acridinyl hydrazides as potent aspartic protease inhibitors.
abstract: 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 IC(50) values against cathepsin D and plasmepsin-II of compound-Nar103 were found to be 9.0+/-2.0 and 4.0+/-1.0nM and of compound-Nar110 were 0.5+/-0.05 and 0.13+/-0.03nM, 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.
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan. mkamranazim@yahoo.co.uk
authors.forename: M Kamran
authors.initials: MK
authors.lastname: Azim
authors.forename: Waseem
authors.initials: W
authors.lastname: Ahmed
authors.forename: Ishtiaq A
authors.initials: IA
authors.lastname: Khan
authors.forename: Nosheen A
authors.initials: NA
authors.lastname: Rao
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Khan
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D002384:Catalysis; D002402:Cathepsin D / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000166:Acridines; D000962:Antimalarials; D006834:Hydrazines; D008024:Ligands; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II; D002402:Cathepsin D