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Ž . ABSTRACT: The very potent HIV-1 protease HIV-PR inhibitor, KNI-272, contains a norstatine]thioproline linkage at P ]P . The three-dimensional crystal 1 1 structure of this compound bound to HIV-PR has recently been determined w Ž .x Baldwin et al., Structure, 3, 581 1995 . The crystal structure reveals a number of interesting interactions previously unseen in bound HIV-PR inhibitors. Here, we employ high-level ab initio calculations and molecular modeling to ascertain the strain energy of the bound conformation of the norstatine]thioproline portion of KNI-272. Baldwin et al. suggested that two of the reasons for the high potency of KNI-272 are the rigidity of its backbone and a strong preference for the norstatine]thioproline amide linkage to adopt a trans conformation. Our analysis shows that, on the contrary, there is still considerable flexibility in the backbone of the norstatine-based inhibitor. Furthermore, in the gas phase and in solution, there are both cis and trans conformations of the norstatine]thioproline amide linkage which are low in energy. However, when bound in the active site of HIV-PR, KNI-272 clearly has a strong preference for a trans conformation, which enables the formation of hydrogen bonds to the flap water. Our calculations, at level up to MP2r6-31qqGrrHFr6-31G , suggest that the bound, trans amide conformation of the norstatine]thioproline ‘‘core’’ is still strained by 2]3 kcalrmol, primarily due to the placement of the P thioproline 1 carboxamide. This result is consistent with those previously obtained for the Ž . related protease inhibitor Ro 31-8959 Saquinovir , which also requires a carboxamide to adopt a high-energy rotamer to preserve a good hydrogen bond to the flap water. However, the strain of the bound conformation of KNI-272 is clearly lower than that of Saquinovir. In addition, because the norstatine linkage

Conformational analysis of HIV-1 protease inhibitors: 2. Thioproline P1 Residue in the potent inhibitor KNI-272