INFLUENCE OF STEREOCHEMISTRY ON ACTIVITY AND BINDING MODES FOR C(2) SYMMETRY-BASED DIOL INHIBITORS OF HIV-1 PROTEASE

The incorporation of C-2 Symmetry has become a useful paradigm in the design of active site inhibitors for HIV-1 protease (HIV PR) and has led to the design of a series of highly potent, C-2 symmetry-based, diol-containing inhibitors of HIV PR, one of which, A-77003, has reached clinical trials. However, the stereochemistry of the diol core influences protease inhibition and antiviral activity in a manner that is not well understood. We analyzed the crystal structures of a diastereomeric series of C-2 symmetry-based diol inhibitors, along with a deshydroxy analogue, bound to HIV PR and found that the stereochemistry of the diol core influences the mode of binding to the active site aspartic acids. Diasteromers with similar binding affinity can bind in different, asymmetric and symmetric, modes, while those with different binding affinities can bind in a similar manner. The positional symmetry of an inhibitor with respect to the enzyme C-2 axis may be distinguished from its conformational symmetry. The structural differences between the inhibitor complexes were mainly confined to the central core portion of the diols, can be described by torsional differences about the central three bonds, and primarily affect interactions within the active site pocket formed by Asp 25/125 and Gly 27/127. Some flexibility in the enzyme backbone at Gly 127 was also apparent. Based on these results, we suggest that the binding mode for central hydroxy-bearing, C-2-symmetric inhibitors will be determined by how well the inhibitor can simultaneously optimize hydrogen bonding with the active site carboxylate groups and van der Waals contacts with the neighboring backbone atoms of the active site ''psi''-loops. A symmetric hydrogen-bonding arrangement with either one or tio symmetrically positioned hydroxy groups appears to be preferred over less symmetric configurations.