A SERIES OF PENICILLIN-DERIVED C2-SYMMETRICAL INHIBITORS OF HIV-1 PROTEINASE - STRUCTURAL AND MODELING STUDIES

The binding modes of a series of penicillin-derived C2 symmetric dimer inhibitors of HIV-1 proteinase were investigated by NMR, protein crys tallography, and molecular modeling. The compounds were found to bind in a symmetrical fashion, tracing an S-shaped course through the activ e site, with good hydrophobic interactions in the S1/S1' and S2/S2' po ckets and hydrogen bonding of inhibitor amide groups. Interactions wit h the catalytic aspartates appeared poor and the protein conformation was very similar to that seen in complexes with peptidomimetics, in sp ite of the major differences in ligand structure.