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Dynamic Pharmacophore Model Optimization: Identification of Novel HIV-1 Integrase Inhibitors

2006; American Chemical Society; Volume: 49; Issue: 5 Linguagem: Inglês

10.1021/jm0510629

1520-4804

Jinxia Deng, Tino W. Sanchez, Nouri Neamati, James M. Briggs,

Biochemical and Molecular Research

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 μM) and 235 (IC50 > 100 μM) 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 ≤ 10 μM for strand transfer reaction.