The capability to propose feasible ways of binding a putative ligand inhibitor to a known receptor site is crucial to the successful structure-based drug design. A computer docking approach is to position or "dock" ligand and receptor molecules together in many different ways and then score each orientation by applying a reasonable evaluation function. AutoDock3.0 is an unbiased type docking program in which a user does not have to direct a ligand to an active site, but the system finds an optimal position after a ligand is placed in a random manner. Synthesized derivatives of the intact inhibitor (inh1) of HIV protease were investigated for their docking modes as compared with their Ki values. Among the derivatives, inh3trans and inh6H were found to be more powerful inhibitors of HIV protease than the others. Gibbs free energy calculated by applying molecular mechanics interaction energies was compared with the one obtained by using experimental inhibitory potencies for a series of HIV protease inhibitors, and a fairly good correlation was found between the two. Based on this favorable correlationship between the computational and the experimental results, the computational experiments were pursued for the compounds drawn by Sybyl taking into consideration the fact that unexploited carbon affinity regions (or hydrophobic regions) with sizable volume were detected on the docking study of inh1 and inh8 against HIV protease. Those were compounds with a t-butyl substituted by various hydrophobic side chains. Among those a compound with a benzyl group exhibited the lowest docking energy. Since one of the goals of this paper was to perform the computational drug-design experiment to investigate potential HIV protease inhibitors, the authors would like to leave the clinical investigational work for the expertise of those areas.
The feline immunodeficiency virus (FIV) protease is essential for virion maturation and subsequent viral replication in that it cleaves the Gag and Gag/Pol polyproteins at eight sites to release the respective structural proteins and enzymes. During purification of a recombinant FIV protease (PR), we noted that it underwent autoproteolysis (autolysis) to give discrete cleavage products. These additional PR cleavage sites were defined using N-terminal amino acid sequence analysis and mass spectrometry. Protease breakdown products were also found in FIV virions and were of the same apparent molecular weights as the in vitro autolysis products. Four primary PR autolysis sites were blocked via substitution of either the P1 amino acid with a -branched amino acid or the P1 amino acid with lysine. Cleavage-resistant PRs which had K m and k cat values similar to those of FIV PR were constructed. An autolysis time course determined that blocking all four primary autolysis sites yielded a cleavage-resistant PR which was enzymatically stable. Concomitant with autolysis is the generation of an N-terminally truncated form of the PR (Thr6/PR) which has enhanced stability with respect to that of FIV PR. A structural basis for the Thr6/PR activity is presented, as are the possible roles of autolysis in the viral replication cycle.
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