Skip to main content
U.S. flag

An official website of the United States government

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

Computational Study of KNI-272, a Potent Inhibitor of HIV-1 Protease. On the Mechanism of Preorganization



L David, R Luo, M S. Head, M K. Gilson


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 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 study 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. Moreover, we find that 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 mutants of KNI-272 provide information on the mechanism of preorganization. Steric interactions among the bulky side-chains of KNI-272 are found to be particularly important in preorganizing the molecule for binding.
Journal of Physical Chemistry


calculation, confirmation, free energy, HIV protease, KNI-272, preorganization


David, L. , Luo, R. , Head, M. and Gilson, M. (1999), Computational Study of KNI-272, a Potent Inhibitor of HIV-1 Protease. On the Mechanism of Preorganization, Journal of Physical Chemistry (Accessed April 15, 2024)
Created February 10, 1999, Updated October 12, 2021