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Mining the NCI antiviral compounds for HIV-1 integrase inhibitors

  1. Author:
    Deng, J. X.
    Kelley, J. A.
    Barchi, J. J.
    Sanchez, T.
    Dayam, R.
    Pommier, Y.
    Neamati, N.

  2. Author Address

    Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA. NCI, Canc Res Ctr, Med Chem Lab, Ft Detrick, MD 21702 USA. NCI, Canc Res Ctr, Mol Pharmacol Lab, Bethesda, MD 20892 USA Neamati, N, Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, 1985 Zonal Ave, Los Angeles, CA 90089 USA
    1. Year: 2006
    2. Date: JUN 1
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 14
    2. 11
    3. Pages: 3785-3792
  4. Type of Article: Article
  1. Abstract:

    HIV-1 integrase (IN) is an essential enzyme for effective viral replication and is it validated target for the development of antiretroviral drugs. Currently, there are no approved drugs targeting this enzyme. In this study, we have identified I I structurally diverse small-molecule inhibitors of IN. These compounds have been selected by mining the moderately active antiviral molecules from a collection of 90,000 compounds screened by the National Cancer Institute (NCI) Antiviral Program. These compounds, which were screened at the NCI during the past 20 years, resulted in approximately 4000 compounds labeled as 'moderately active.' In our study, chalcone I I shows the most potent activity with an IC50 of 2 +/- 1 mu M against purified IN in the presence of both Mn2+ and Mg2+ as cofactors. Docking simulations using the I I identified inhibitors as a training set have elucidated two unique binding areas within the active site: The first encompasses the conserved D64-D116-E152 motif, while the other involves the flexible loop region formed by amino acid residues 140-149. The tested inhibitors exhibit favorable interactions with important amino acid residues through van der Waals and H-bonding contacts. (c) 2006 Elsevier Ltd. All rights reserved

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External Sources

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  2. DOI: 10.1016/j.bmc.2006.01.040
  3. View record in Web of Science®
  4. WOS: 000237498500017

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