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

Abstract

The very potent HIV-1 protease (HIV-PR) inhibitor, KNI-272, contains a norstatine–thioproline linkage at P1–P1′. The three-dimensional crystal structure of this compound bound to HIV-PR has recently been determined [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 MP2/6-31++G//HF/6-31G*, suggest that the bound, trans amide conformation of the norstatine–thioproline “core” is still strained by 2–3 kcal/mol, primarily due to the placement of the P1′ thioproline carboxamide. This result is consistent with those previously obtained for the 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 does not contain a basic amine (as do Saquinovir and JG-365, for example) it should be easier to desolvate, which also assists in binding. The relationship between KNI-272, JG-365, Saquinovir, and P1′ proline-containing substrate also is discussed. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1151–1166