title: Pentacycloundecane derived hydroxy acid peptides: a new class of irreversible non-scissile ether bridged type isoster as potential HIV-1 wild type C-SA protease inhibitors.
abstract: Novel peptides incorporating the PCU derived hydroxy acid (5-hydroxy-4-oxahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane) were synthesized and their activity against the resistance-prone wild type C-South African (C-SA) HIV-protease is reported. The attachment of peptides and peptoids to the PCU derived hydroxy acid resulted in a series of structurally diverse promising HIV-1 protease inhibitors. Amongst the nine novel compounds, 16, 17, 20 and 23 gave IC(50) values ranging from 0.6 to 5.0 μM against the wild type C-SA HIV-1 protease enzyme. Docking studies and molecular dynamic (MD) simulations have been carried out in order to understand the binding mode of the PCU moiety at the active site of the HIV protease enzyme. A conserved hydrogen bonding pattern between the PCU derived hydroxy ether and the active site residues, ASP25/ASP25', was observed in all active compounds.
authors: School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Rajshekhar
authors: R
authors: Karpoormath
authors: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Wits 2050, South Africa.
authors: Yasien
authors: Y
authors: Sayed
authors: School of Biochemistry, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Patrick
authors: P
authors: Govender
authors: School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Thavendran
authors: T
authors: Govender
authors: School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Hendrik G
authors: HG
authors: Kruger
authors: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address: mess20@bath.ac.uk.
authors: Mahmoud E S
authors: MES
authors: Soliman
authors: School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa. Electronic address: maguireg@ukzn.ac.za.
authors: Glenn E M
authors: GEM
authors: Maguire
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D004986:Ether / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D006880:Hydroxy Acids / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D006880:Hydroxy Acids; D010455:Peptides; D004986:Ether; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1