Inhibitors Reduced binding affinity

While the effect of primary mutations on reduced binding affinities of inhibitors can be at least partially explained in view of the accumulated structural data, the function of secondary, or compensatory mutations in the resistant HIV PR is difficult to rationalize as yet. The predominant compensatory mutations observed in the resistant variants involve residues Leu63/63, 1 71/7 , Met46/46, ... 

Analysis of the components of the relative binding free energy reveals some interesting details regarding the loss in binding affinity due to mutation. It is found that the I84V mutant enzyme in all cases is more stable than the wild type enzyme (Table 3 Column 2). Since the mutant enzyme is more stable (by 0.7 to 3 kcal/mol) it will have less of a tendency to bind than the wild type enzyme. This fact alone (independent of the inhibitor association with the enzyme) can be used to qualitatively explain the reduced binding affinity due to mutation. The... 

Several PKC effects were obtained from conclusions vdiich are not substantiated by experiments. If the photoaffinity labeling with azidopine is decreased by a PKC inhibitor which reverses MDR, it may be concluded that the inhibitor competes with azidopine by binding to PGP. However, it can also be concluded that the PKC inhibitor reduces the phosphorylation of PGP and that, due to altered affinity of unphosphorylated PGP to drugs, less azidopine binds to PGP. If a PKC inhibitor reverses MDR, it may be concluded that the reversal is due to inhibition of PKC and reduced PGP phosphorylation. However, a PKC inhibitor might also reduce the drug efflux by direct interaction with PGP. There are several possibilities how a PKC inhibi-... 

When fructose 2,6-bisphosphate binds to its allosteric site on PFK-1, it increases that enzyme s affinity for its substrate, fructose 6-phosphate, and reduces its affinity for the allosteric inhibitors ATP and citrate. At the physiological concentrations of its substrates ATP and fructose 6-phosphate and of its other positive and negative effectors (ATP, AMP, citrate), PFK-1 is virtually inactive in the absence of fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate activates PFK-1 and stimulates glycolysis in liver and, at the same time, inhibits FBPase-1, thereby slowing gluconeogenesis. 

More recently, an approach to replace the thioether in FTP with a triazole was attempted utilizing a dipolar cycloaddition to join the prenyl and carboxylate groups [57]. These analogs are not substrates for Icmt, but all possess some activity as inhibitors. Despite the dramatic shift from the thioether to the triazole, the most potent compound retains significant binding affinity and is able to reduce Icmt activity by approximately 50%... 

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