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Molecular modelling studies of synthesized pentacyclo-undecane peptides as potential HIV-1 wild type C-SA protease inhibitors

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Increasing numbers of HIV infected patients along with severe treatment-associated complications and related deaths make the AIDS pandemic [1]. These inhibitors reduced the virus proliferation and this success made the HIV aspartic protease the prime target for AIDS therapies [2]. In this study, we present the first account of pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors with nanomolar activity against the resistance-prone wild type C-South African HIV-protease (C-SA). NMR and molecular docking were employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. In addition, docking studies confirmed the observed EASY-ROESY results and the experimental IC50 activity profile of the considered inhibitors. Due to theoretical importance of nuclear quadrupole resonance data [3] for characterization of molecular dynamics, DFT calculations are carried out to obtain 17O and 14N- NQR parameters. The studies reported in this work were undertaken to establish whether the NQR method could be used to derive a rational structure-activity relationship for these inhibitors. These findings open up useful applications for this family of inhibitors, considering the vast number of alternative disease related proteases that may exist.

References

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    Wlodawer A, Vondrasek J: Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomolec Struct. 1998, 27: 249-284. 10.1146/annurev.biophys.27.1.249.

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    Velaquez-Campoy A, Vega S, Fleming E, Bacha U, Sayed Y, Dirr HW, Freire E: Protease inhibition in African subtypes of HIV-1. Aids Rev. 2003, 5: 165-171.

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    Harris RK: Nuclear Magnetic Resonance Spectroscopy, A physicochemical view. 1983, Pitman: London

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Correspondence to Bahareh Honarparvar.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Honarparvar, B., Kruger, H.G., Soliman, M.E. et al. Molecular modelling studies of synthesized pentacyclo-undecane peptides as potential HIV-1 wild type C-SA protease inhibitors. J Cheminform 5, P1 (2013) doi:10.1186/1758-2946-5-S1-P1

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Keywords

  • Molecular Docking
  • Nuclear Quadrupole Resonance
  • Aspartic Protease
  • Molecular Modelling Study
  • Virus Proliferation