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Computational POM and 3D-QSAR evaluation of experimental in vitro HIV-1-Integrase inhibition of amide-containing diketoacids

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Abstract

A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-viral candidates based on available X-ray structures of drugs. The compounds have been previously screened for anti-viral activity against HIV-Integrase (HIV IN). Amongst the series, the most potent compounds, 4k and 4d (low μM IC50) were tested in viral cultures for their ability to present potentials (O δ−1 –O δ−2 –O δ−3 ) for anti-viral pharmacophore site but represent a potential risk of toxicity. Furthermore, the compounds 4k and 4d showed potent anti-HIV IN activity. A good correlation was obtained between the theoretical predictions of bioavailability using POM suite (Petra/Osiris/Molinspiration containing Lipinski’s rule-of-five) and experimental verification. The structure–activity relationships were also analyzed to vindicate the POM results.

Graphical abstract

A series of known anti-HIV agents; the amide-containing diketoacids were POM and 3D-QSAR analyzed in goal to understand and develop more potent/selective HIV IN inhibitors. Their inhibition of HIV IN was attributed to them containing O1,O2,O4-pharmacophore site. The structure–activity relationships were discussed on the basis of POM analyses.

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Acknowledgments

The authors thank the Mohammed First University Research Council for financial support (Grant Ref.: PGR-BH). Prof. T. Ben Hadda would like to thank ACTELION; the Biopharmaceutical Company of Swiss, for the on-line molecular properties calculations.

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Authors and Affiliations

  1. Laboratoire Chimie Matériaux, FSO, Université Mohammed 1ier, 60000, Oujda, Morocco

    Taibi Ben Hadda & Jihane Fathi

  2. Universiapolis, Bab Al Madine, Quartier Tilila, BP 8143, Agadir, Morocco

    Imane Chafchaouni

  3. Department of Chemistry, Vidya Bharati College, Amravati, 444602, Maharashtra, India

    Vijay Masand

  4. Laboratoire Chimie Plantes Synthèse Organique et Bioorganique, FS, Rabat, Morocco

    Zoubida Charrouf

  5. Department of Chemistry, Bahauddin Zakariya University, Multan, 60800, Pakistan

    Zahid H. Chohan

  6. Department of Pharmaceutical Chemistry, Sahyadri College of Pharmacy, Sangola, Solapur, Maharashtra, India

    Rahul Jawarkar

  7. Laboratoire de Chimie Physique des Biomolécules et Interfaces Biologiques, Faculté des Sciences de la Nature et de la Vie, Université de Mascara, 29000, Mascara, Algeria

    Teffaha Fergoug

  8. Department of Chemistry, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia

    Ismail Warad

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  1. Taibi Ben Hadda
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  2. Jihane Fathi
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  6. Zahid H. Chohan
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  7. Rahul Jawarkar
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Correspondence to Taibi Ben Hadda or Vijay Masand.

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Hadda, T.B., Fathi, J., Chafchaouni, I. et al. Computational POM and 3D-QSAR evaluation of experimental in vitro HIV-1-Integrase inhibition of amide-containing diketoacids. Med Chem Res 22, 1456–1464 (2013). https://doi.org/10.1007/s00044-012-0120-0

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  • DOI: https://doi.org/10.1007/s00044-012-0120-0

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