Functional design of potential inhibitors of human immunodeficiency virus (HIV) binding to CD4+ target cells: a molecular model of gp120 predicts ligand binding.

Inhibition of binding of HIV via gp120 to its principle cellular receptor, CD4, remains an attractive site for intervention in the viral replicative cycle despite the poor clinical trial results demonstrated to date for sCD4. Based on a model structure we recently proposed for gp120, we have examined the predicted binding sites for several synthetic and natural products which selectively bind to gp120 and inhibit binding to CD4. Correlation between the decrease in internal energies of the ligand/gp120 complexes versus the reported inhibitory constants of the known ligands suggests that the derived gp120 structure is sufficiently accurate to perform computer simulations to guide the design of improved ligands for the CD4 binding site on gp120.