Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1

Recent X-ray crystallographic determination of the HIV-1 envelope glycoprot ein gp41 core structure opened up a new avenue to discover antiviral agents for chemotherapy of HIV-1 infection and AIDS. We have undertaken a systema tic study to search for anti-HIV-1 lead compounds targeted to gp41. Using m olecular docking techniques to screen a database of 20 000 organic molecule s, we found 16 compounds with the best fit for docking into the hydrophobic cavity within the gp41 core and with maximum possible interactions with th e target site. Further testing of these compounds by an enzyme-linked immun osorbent 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 comp ounds will be used as leads to design more effective HIV-1 inhibitors targe ted to the HIV-1 gp41 core structure.