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Cited by 259

The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.

Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

Open access
Carlson, Heather A., Masukawa, Kevin M., Rubins, Kathleen, Bushman, Fredric D., Jorgensen, William L., Lins, Roberto D., Briggs, James M., McCammon, J. Andrew·2000·Journal of Medicinal Chemistry
DOI 10.1021/jm990322h
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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 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.

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Metadata

Authors
Carlson, H. A., Masukawa, K. M., Rubins, K., Bushman, F. D., Jorgensen, W. L., Lins, R. D., Briggs, J. M., & McCammon, J. A.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2000-05-11
Volume
43
Issue
11
Pages
2100-2114
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm990322h
OpenAlex
W1977173978
Cited by
259
References
68
FWCI
12.60
Type
journal article
Language
en
Open access
green

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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