Dynamic pharmacophore model optimization: Identification of novel HIV-1 integrase inhibitors
Dynamic pharmacophore model optimization: Identification of novel HIV-1 integrase inhibitors
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DOI：
10.1021/jm0510629
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发表时间：
2006-03-09
影响因子：
7.3
通讯作者：
Briggs, JM
中科院分区：
文献类型：
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作者：
Deng, JX;Sanchez, T;Briggs, JM
我们扩展了先前描述的HIV-1整合酶（IN）的动态药效团模型研究，考虑更多的关键残基的活性位点，包括Mg 2+。首先，我们应用蒙特卡罗抽样方法来映射IN结合表面的互补特征。生成了两种类型的动态药效团模型。一种认为Mg 2+是IN的一部分，因此是排除的体积，另一种认为Mg 2+是带正电荷的特征，代表了一种新型的药效团模型，旨在鉴定可能阻止Mg 2+结合的化合物。其次，我们用385种已知的活性（IC 50 < 20 μ M）和235种（IC 50> 100 μ M）非活性IN抑制剂验证了模型。第三，我们使用衍生的模型来筛选我们的小分子数据库。在对IN特异性的体外测定中测试了22种结构新颖的化合物，其中两种显示出IC 50
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 mu M) and 235 (IC50 > 100 mu M) 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