Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

• Published in: Journal of medicinal chemistry Vol. 43; no. 11; pp. 2100 - 2114
• Main Authors: Carlson, Heather A, Masukawa, Kevin M, Rubins, Kathleen, Bushman, Fredric D, Jorgensen, William L, Lins, Roberto D, Briggs, James M, McCammon, J. Andrew
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.06.2000
• Subjects: AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Computer Simulation; CRYSTAL STRUCTURE; Drug Evaluation, Preclinical; ENVIRONMENTAL MOLECULAR SCIENCES LABORATORY; FLEXIBILITY; FUNCTIONALS; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; Human immunodeficiency virus 1; MANAGEMENT OF RADIOACTIVE WASTES, AND NON-RADIOACTIVE WASTES FROM NUCLEAR FACILITIES; MATERIALS SCIENCE; Medical sciences; MINIMIZATION; Models, Chemical; Models, Molecular; MONOCRYSTALS; Pharmacology. Drug treatments; PROBES; Protein Conformation; PROTEINS; SIMULATION; Structure-Activity Relationship; TARGETS; TESTING; HIV-1 virus; Enzyme; Active site; Molecular dynamics method; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Modeling; Research and development; Virus; Structure activity relation; Molecular model; Antiviral; Human immunodeficiency virus; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990322h

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.