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Title: Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

Abstract

We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of ''dynamic'' pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a ''static'' pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active sitemore » of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab., Richland, WA (US), Environmental Molecular Sciences Laboratory (US)
Sponsoring Org.:
US Department of Energy (US)
OSTI Identifier:
15010435
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 43; Journal Issue: 11; Other Information: PBD: 11 May 2000; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
English
Subject:
12 MANAGEMENT OF RADIOACTIVE WASTES, AND NON-RADIOACTIVE WASTES FROM NUCLEAR FACILITIES; 36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; FLEXIBILITY; FUNCTIONALS; MINIMIZATION; MONOCRYSTALS; PROBES; PROTEINS; SIMULATION; TARGETS; TESTING; ENVIRONMENTAL MOLECULAR SCIENCES LABORATORY

Citation Formats

Carlson, Heather A., Masukawa, Keven M., Rubins, Kathleen, Bushman, Frederic, Jorgensen, William L., Lins, Roberto, Briggs, James, and Mccammon, Andy. Developing a Dynamic Pharmacophore Model for HIV-1 Integrase. United States: N. p., 2000. Web. doi:10.1021/jm990322h.
Carlson, Heather A., Masukawa, Keven M., Rubins, Kathleen, Bushman, Frederic, Jorgensen, William L., Lins, Roberto, Briggs, James, & Mccammon, Andy. Developing a Dynamic Pharmacophore Model for HIV-1 Integrase. United States. doi:10.1021/jm990322h.
Carlson, Heather A., Masukawa, Keven M., Rubins, Kathleen, Bushman, Frederic, Jorgensen, William L., Lins, Roberto, Briggs, James, and Mccammon, Andy. Thu . "Developing a Dynamic Pharmacophore Model for HIV-1 Integrase". United States. doi:10.1021/jm990322h.
@article{osti_15010435,
title = {Developing a Dynamic Pharmacophore Model for HIV-1 Integrase},
author = {Carlson, Heather A. and Masukawa, Keven M. and Rubins, Kathleen and Bushman, Frederic and Jorgensen, William L. and Lins, Roberto and Briggs, James and Mccammon, Andy},
abstractNote = {We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of ''dynamic'' pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a ''static'' pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors.},
doi = {10.1021/jm990322h},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 11,
volume = 43,
place = {United States},
year = {2000},
month = {5}
}