Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type 1

• Published in: Journal of medicinal chemistry 1999-08, Vol.42 (17), p.3203-3209
• Main Authors: Debnath, Asim Kumar, Radigan, Lin, Jiang, Shibo
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Fusion - drug effects; Cell Line; Enzyme-Linked Immunosorbent Assay; glycoprotein gp41; HIV Envelope Protein gp41 - chemistry; HIV Envelope Protein gp41 - metabolism; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Medical sciences; Models, Molecular; Molecular Conformation; Naphthalenesulfonates - chemistry; Pharmacology. Drug treatments; Structure-Activity Relationship; Triazines - chemistry
• ISSN: 0022-2623; 1520-4804
• 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.