Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1
Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1
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DOI：
10.1021/jm990154t
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发表时间：
1999-08-26
影响因子：
7.3
通讯作者：
Jiang, SB
中科院分区：
文献类型：
--
作者：
Debnath, AK;Radigan, L;Jiang, SB
最近对HIV-1包膜糖蛋白gp41核心结构的x射线晶体学测定为发现HIV-1感染和艾滋病化疗的抗病毒药物开辟了新的途径。我们已经进行了一项系统的研究，以寻找靶向gp41的抗hiv -1先导化合物。利用分子对接技术对数据库中的2万个有机分子进行筛选，我们发现了16个最适合与gp41核心的疏水腔对接的化合物，并与目标位点进行了最大可能的相互作用。通过酶联免疫吸附试验和病毒抑制试验对这些化合物进行进一步测试，发现两种化合物（ADS-J1和ADS-J2）在微摩尔浓度下对gp41核心结构的形成和HIV-1感染具有抑制活性。这两种化合物将用于设计针对HIV-1 gp41核心结构的更有效的HIV-1抑制剂。
Recent X-ray crystallographic determination of the HIV-1 envelope glycoprotein gp41 core structure opened up a new avenue to discover antiviral agents for chemotherapy of HIV-1 infection and AIDS. We have undertaken a systematic study to search for anti-HIV-1 lead compounds targeted to gp41. Using molecular docking techniques to screen a database of 20 000 organic molecules, we found 16 compounds with the best fit for docking into the hydrophobic cavity within the gp41 core and with maximum possible interactions with the target site. Further testing of these compounds by an enzyme-linked immunosorbent assay and virus inhibition assays discerned two compounds (ADS-J1 and ADS-J2) having inhibitory activity at micromolar concentrations on the formation of the gp41 core structure and on HIV-1 infection. These two compounds will be used as leads to design more effective HIV-1 inhibitors targeted to the HIV-1 gp41 core structure.