Computer-aided design, synthesis, and biological activity evaluation of potent fusion inhibitors targeting HIV-1 gp41

This discovered and optimized several novel HIV-1 fusion inhibitors and further evaluated the inhibitory activities of these compounds in vitro. Here, we have reported the computer-aided design, synthesis, and biological evaluation of a series of small molecule fusion inhibitors targeting HIV-1 gp41. Based on the structure of inhibitor (NB2), we carried out de novo design and screened out a series of novel structure molecules by using Leapfrog and Autodock programs. Our structure-based modification obtained a potent fusion inhibitor (IC₅₀ = 41.1 µg/mL). Several novel compounds were discovered as fusion inhibitors, which suggested that our design methodology is reliable, paving the way for de novo design of novel small-molecule HIV inhibitors targeting gp41.