Dynamic Pharmacophore Model Optimization: Identification of Novel Hiv-1 Integrase Inhibitors.
From: Department of Chemical Engineering, University of Houston, Houston, Texas 77204, USA.
Journal of medicinal chemistry
- Publish Date: Mar 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 5
- Pages: 1684-92
- Medium: Print
- Language: English
- Citation (JAMA): Deng Jinxia, Sanchez Tino, Neamati Nouri, et al. Dynamic Pharmacophore Model Optimization: Identification of Novel Hiv-1 Integrase Inhibitors.. J. Med. Chem. Mar 2006;49:1684-92
Abstract
We extended the previously described dynamic pharmacophore model studies of HIV-1 integrase (IN) by considering more key residues in the active site, including Mg2+. First, we applied a Monte Carlo sampling method to map the complementary features of the IN binding surface. Two types of dynamic pharmacophore models were generated. One considers Mg2+ as part of the IN and therefore as an excluded volume, and the other treats Mg2+ as a positively charged feature, representing a new type of pharmacophore model aimed to identify compounds potentially preventing Mg2+ binding. Second, we validated the models with 385 known active (IC50 < 20 microM) and 235 (IC50 > 100 microM) inactive IN inhibitors. Third, we used the derived models to screen our small molecule database. Twenty-two structurally novel compounds were tested in an in vitro assay specific for IN, and two of them showed IC50 < or = 10 microM for strand transfer reaction.
Mesh Headings (Keywords): Algorithms, Anthraquinones, Binding Sites, Cations, Divalent, Databases, Factual, HIV Integrase, HIV Integrase Inhibitors, Magnesium, Models, Molecular, Monte Carlo Method, Protein Binding, Pyrazoles
Check for Full Text / PubMed Unique Identifier (PMID): 16509584
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