Computational study of KNI-272, a potent inhibitor of HIV-1 protease: On the mechanism of preorganization

The compound KNI-272 is a potent, peptide-like inhibitor of HIV protease. Its conformation when complexed with the protease is close to that which it assumes in its single-molecule crystal. This observation led to the suggestion that KNI-272 gains affinity by being preorganized for binding. On the other hand, one might well expect KNI-272 to be flexible because it possesses 15 rotatable bonds. Moreover, a recent ab initio study of KNI-272 suggests that it is not preorganized because its bound conformation is strained. Here, we use a novel algorithm to study the conformational distribution of this inhibitor. The results show good agreement with a recent NMR analysis of KNI-272 in solution. The calculations indicate that KNI-272 in solution occupies three major conformations, one of which matches the bound conformation and the NMR structure. In addition, the thioproline amide bond tends to be in the trans conformation found in the complex of KNI-272 with HIV protease. Further calculations on hypothetical analogues of KNI-272 provide information on the mechanism of preorganization and indicate that steric interactions among the bulky side chains are of particular importance.