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

✍ Scribed by Mark A. Murcko; B. Govinda Rao

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: English
• Weight: 719 KB
• Volume: 14
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.540141206

✦ Synopsis

Pipecolic acid derivatives have proven to be effective Pi 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 Pi 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. SpecMcally, 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 Naxial 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 Nequatorial 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.