Debnath A K, Radigan L, Jiang S
Lindsley F. Kimball Research Institute, The New York Blood Center, 310 East 67th Street, New York, New York 10021, USA.
J Med Chem. 1999 Aug 26;42(17):3203-9. doi: 10.1021/jm990154t.
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.
最近通过X射线晶体学对HIV-1包膜糖蛋白gp41核心结构的测定，为发现用于HIV-1感染和艾滋病化疗的抗病毒药物开辟了一条新途径。我们开展了一项系统性研究，以寻找靶向gp41的抗HIV-1先导化合物。利用分子对接技术筛选了一个包含20000个有机分子的数据库，我们发现有16种化合物与gp41核心内的疏水腔对接最为匹配，且与靶位点具有最大可能的相互作用。通过酶联免疫吸附测定和病毒抑制试验对这些化合物进行进一步测试，识别出两种化合物（ADS-J1和ADS-J2）在微摩尔浓度下对gp41核心结构的形成以及HIV-1感染具有抑制活性。这两种化合物将作为先导物用于设计更有效的靶向HIV-1 gp41核心结构的HIV-1抑制剂。
