Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV-1 gp120

The small-molecule CD4 mimetics (smCD4mcs) are a class of highly potent HIV-1 entry inhibitors characterized by a unique structure-activity relationship (SAR). They share a halogenated phenyl ring (region1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, the so-called F43 cavity. Conservative modifications to region1 away from this halogenated phenyl motif have all led to loss of activity, despite the fact that they are predicted by standard empirical computational approaches to bind equally well, making it difficult to further optimize this region of the compounds to increase binding to gp120. In this study we used quantum mechanical methods to understand the roots of the interactions between region1 and the F43 cavity. We clearly demonstrate the presence of halogen bond/sigma-hole and dispersion interactions between region1 and the F43 cavity residues F376-N377, which are not captured by standard molecular mechanics approaches and the role played by the smCD4mc in the F43 cavity desolvation. These findings rationalize why the halogenated region1 has proven so difficult to move beyond in smCD4mc optimization, in agreement with experimental evidence.