CONFORMATIONAL-ANALYSIS OF HIV PROTEASE INHIBITORS .1. ROTATION OF THE AMIDE GROUP ADJACENT TO THE P-1(') DECAHYDROISOQUINOLINE RING-SYSTEMIN RO-31-8959 AND RELATED SYSTEMS

Pipecolic acid derivatives have proven to be effective P1' groups in a series of highly potent inhibitors of the enzyme HIV protease. One su ch inhibitor, Ro 31-8959, contains the saturated bicyclic ring system decahydroisoquinoline (DIQ) in the P1' position. The binding orientati on of Ro 31-8959 is known from X-ray crystallography. However, the bou nd conformation of the S-hydroxy diastereomer has not been studied, an d for this molecule there are at least two different possible binding conformations. Specifically, the N-alkyl substituents may be equatoria l 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 calculati ons have been carried out on a series of pipecolic acid and DIQ deriva tives. The results indicate that the lowest-energy N-equatorial rotame r is always at least 3 kcal/mol more stable than the lowest-energy N-a xial rotamer. The presence of the second ring, as in the DIQ system, c onsiderably raises the equatorial-axial difference to nearly 7 kcal/mo l. Also, the preferred rotation angle of the amide group is different for the N-equatorial and N-axial cases. When the molecular dynamics-av eraged conformation of the bound S-hydroxy inhibitor is considered, th e energy difference between the N-equatorial and N-axial conformers dr ops to 4-5 kcal/mol. The preferred amide rotations in these systems ar e compared to those found in proline-containing peptides. Finally, som e observations are made with respect to the large conformational energ y penalty necessary for binding Ro 31-8959. (C) 1993 by John Wiley & S ons, Inc.