β-Diketo acid pharmacophore hypotesis.: 1.: Discovery of a novel class of HIV-1 integrase inhibitors
β-Diketo acid pharmacophore hypotesis.: 1.: Discovery of a novel class of HIV-1 integrase inhibitors
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DOI：
10.1021/jm0496077
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发表时间：
2005-01-13
影响因子：
7.3
通讯作者：
Neamati, N
中科院分区：
文献类型：
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作者：
Dayam, R;Sanchez, T;Neamati, N
HIV-1整合酶（Integrin ase，IN）是HIV病毒复制所必需的酶。β-二酮酸的发现对于验证IN作为抗HIV感染药物发现的合法靶点至关重要。在这项研究中，我们发现了一类新的IN抑制剂使用3D药效团引导数据库搜索。我们使用S-1360（1），第一个进行临床试验的IN抑制剂，和其他三个类似物来开发一个共同的特征药效团假说。测试这四个功能药效团对150 000个结构不同的小分子的多构象数据库产生了1700个化合物，满足3D查询。随后，所有1700种化合物都被对接到IN的活性位点。基于对接分数，Lipinski的规则，五，和结构新奇，110个化合物被选择用于生物筛选。我们发现含有水杨酸和2-硫代-4-噻唑烷酮（绕丹宁）基团（例如5-13）的化合物显示出对IN的显著抑制效力，而单独存在水杨酸或绕丹宁基团则没有。虽然一些只含有水杨酸的化合物显示出对IN的抑制效力，但没有一种只含有若丹宁的化合物显示出相当大的效力。在本研究中报道的52种化合物中，11种化合物（5、6、8、10-13、32-33、51和53）抑制IN的T加工或链转移活性，IC 50小于或等于25 μ M。这是第一次报道使用S-1360及其类似物作为开发IN抑制药效团假说和鉴定具有该酶强效抑制作用的新化合物的先导物。
HIV-1 Integrase (IN) is an essential enzyme for viral replication. The discovery of beta-diketo acids was crucial in the validation of IN as a legitimate target in drug discovery against HIV infection. In this study, we discovered a novel class of IN inhibitors using a 3D pharmacophore guided database search. We used S-1360 (1), the first IN inhibitor to undergo clinical trials, and three other analogues to develop a common feature pharmacophore hypothesis. Testing this four-featured pharmacophore against a multiconformational database of 150 000 structurally diverse small molecules yielded 1700 compounds that satisfied the 3D query. Subsequently, all 1700 compounds were docked into the active site of IN. On the basis of docking scores, Lipinski's rule-of-five, and structural novelty, 110 compounds were selected for biological screening. We found that compounds that contain both salicylic acid and a 2-thioxo-4-thiazolidinone (rhodanine) group (e.g. 5-13) showed significant inhibitory potency against, IN, while the presence of either salicylic acid or a rhodanine group alone did not. Although some of the compounds containing only a salicylic acid showed inhibitory potency against IN, none of the compounds containing only rhodanine exhibited considerable potency. Of the 52 compounds reported in this study, 11 compounds (5, 6, 8, 10-13, 32-33, 51, and 53) inhibited T-processing or strand transfer activities of IN with IC50 less than or equal to 25 muM. This is the first reported use of S-1360 and its analogues as leads in developing a pharmacophore hypothesis for IN inhibition and for identification of new compounds with potent inhibition of this enzyme.