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Pentacycloundecane‐diol‐Based HIV‐1 Protease Inhibitors: Biological Screening, 2 D NMR, and Molecular Simulation Studies
Author(s) -
Honarparvar Bahareh,
Makatini Maya M.,
Pawar Sachin A.,
Petzold Katja,
Soliman Mahmoud E. S.,
Arvidsson Per I.,
Sayed Yasien,
Govender Thavendran,
Maguire Glenn E. M.,
Kruger Hendrik G.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100512
Subject(s) - lopinavir , protease , proteases , chemistry , docking (animal) , catalytic triad , moiety , stereochemistry , enzyme , peptide , hydrogen bond , human immunodeficiency virus (hiv) , combinatorial chemistry , active site , biochemistry , virology , biology , molecule , organic chemistry , medicine , nursing , viral load , antiretroviral therapy
Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild‐type C‐South African (C‐SA) HIV‐1 protease. Seven compounds are reported herein, three of which displayed IC 50 values in the 0.5–0.6 μ M range. The cytotoxicity of PCU cage peptides toward human MT‐4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through‐space 1 H, 1 H distances/contacts in the EASY‐ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU‐based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.