A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 to identify new inhibitors of gp120–CD4 protein–protein interactions

A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 was built and used to identify new hits able to inhibit gp120–CD4 protein–protein interactions. Two compounds showed micromolar inhibition of HIV-1 replication in cells attributable to an interference with the entry step of infection, by direct interaction with gp120. Inactivity of compounds toward a M475I strain suggested specific contacts with the Phe43 cavity of gp120.

Graphical abstractTwo novel chemical scaffolds targeting the HIV-1 gp120 Phe43 cavity and able to interfere with gp120–CD4 protein–protein interactions were identified by structure-based in silico screening.Figure optionsDownload full-size imageDownload as PowerPoint slide