National Center for
4KB9: Crystal Structure Of Wild-type Hiv-1 Protease With Novel Tricyclic P2- Ligands Grl-0739a
Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein-Ligand X-ray Studies
J. Med. Chem. (2013) 56 p.6792-6802
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.