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Dynamic Receptor-Based Pharmacophore Model Development and Its Application in Designing Novel HIV-1 Integrase Inhibitors

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Department of Chemical Engineering, University of Houston, Houston, Texas 77204-4004, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001, and Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC304A, Los Angeles, California 90089
Cite this: J. Med. Chem. 2005, 48, 5, 1496–1505
Publication Date (Web):February 15, 2005
https://doi.org/10.1021/jm049410e
Copyright © 2005 American Chemical Society
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    Abstract

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    We present here a dynamic receptor-based pharmacophore model representing the complementary features of the active site region of HIV-1 integrase (IN), which was developed from a series of representative conformations of IN. Conformations of IN were sampled through a molecular dynamics study of the catalytic domain of an IN monomer, and an ensemble of representative IN structures were collected via a probability-based representative conformer sampling method that considers both the potential energy and the structural similarity of the protein conformations. The dynamic pharmacophore model was validated by a set of 128 known inhibitors, and the results showed that over 72% of the active inhibitors (IC50 lower than 20 μM) could be successfully identified by the dynamic model. Therefore, we screened our in-house database of commercially available compounds against this model and successfully identified a set of structurally novel IN inhibitors. Compounds 7 and 18 with IC50s of 8 μM and 15 μM, respectively, against the strand transfer reaction were the most potent. Moreover, 7, 8 and 20 showed a 5-fold selectivity for the strand transfer reaction over 3‘-processing.

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    †

     Department of Chemical Engineering, University of Houston.

    §

     University of Southern California.

    ‡

     Department of Biology and Biochemistry, University of Houston.

    ‖

     Current address:  Department of Biochemistry, Gyeongsang National University, 900 Gazwa-dong, Jinju, GN 660−701 Korea.

    *

     Corresponding authors. Neamati:  Tel:  323-442-2341, Fax:  323-442-1390, e-mail:  [email protected]; Briggs:  Tel:  713-743-8366, Fax:  713-743-8351, e-mail:  [email protected].

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    Structures of published inhibitors used in this study to validate our dynamic pharmacophore model are available free of charge via the Internet at http://pubs.acs.org.

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