Conformational analysis of HIV protease inhibitors. I. Rotation of the amide group adjacent to the P′ 1 decahydroisoquinoline ring system in ro 31‐8959 and related systems

Pipecolic acid derivatives have proven to be effective P′ 1 groups in a series of highly potent inhibitors of the enzyme HIV protease. One such inhibitor, Ro 31‐8959, contains the saturated bicyclic ring system decahydroisoquinoline (DIQ) in the P′ 1 position. The binding orientation of Ro 31‐8959 is known from X‐ray crystallography. However, the bound conformation of the S ‐hydroxy diastereomer has not been studied, and for this molecule there are at least two different possible binding conformations. Specifically, the N ‐alkyl substituents may be equatorial or axial and the 3‐carboxamide may be rotated into several different orientations. To gain a better understanding of the relative energies of these various conformations, ab initio molecular orbital calculations have been carried out on a series of pipecolic acid and DIQ derivatives. The results indicate that the lowest‐energy N ‐equatorial rotamer is always at least 3 kcal/mol more stable than the lowest‐energy N ‐axial rotamer. The presence of the second ring, as in the DIQ system, considerably raises the equatorial–axial difference to nearly 7 kcal/mol. Also, the preferred rotation angle of the amide group is different for the N ‐equatorial and N ‐axial cases. When the molecular dynamics‐averaged conformation of the bound S ‐hydroxy inhibitor is considered, the energy difference between the N ‐equatorial and N ‐axial conformers drops to 4–5 kcal/mol. The preferred amide rotations in these systems are compared to those found in proline‐containing peptides. Finally, some observations are made with respect to the large conformational energy penalty necessary for binding Ro 31‐8959. © John Wiley & Sons, Inc.