ISSN:
0018-019X
Keywords:
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The difference between the strong inhibition of retaining β-glucosidases by the tetrazole 1 and the weak inhibition by the triazole 3 has been explained by the protonation by the enzymic catalytic acid of N(3) of 1, replaced by CH in 3. One also expects a contribution to the inhibition from the charge-dipole interaction between the enzymic catalytic nucleophile and the azole ring. The extent of this contribution was estimated from the calculated, distance-dependent heats of formation of the acetate-azole complexes. The calculations were validated by comparison of the charge-dipole interaction between phosphate and the inhibitors 1 and 3 in the glycogen phosphorylase b (GPb)-azole-phosphate complexes, as derived from differences in the Ki values for 1 and 3, while the structural invariance of the complexes was demonstrated by X-ray analysis. The difference between the charge-dipole interactions of (dihydrogen) phosphate and 1 or 3 as derived from Δ Ki is 1.1 kcal mol-1, while the calculated difference is 1.3 kcal mol-1. The calculated difference for the interaction of 1 or 3 with acetate, representing the catalytic nucleophile in β-glycosidases, is 2.0 kcal mol-1, while the differences of the binding energies as derived from the Ki values for the inhibition by 1 or 3 of different β-glycosidases range from 2.4 to 5.3 5 kcal mol-1. The calculated difference for 1 and the imidazole 6 is 2.5 kcal mol-1 in favour of 1, whereas the Ki-derived difference is 3.7 kcal mol-1 in favour of 6, equal to the calculated difference between 1 and the protonated imidazole 6. Thus, protonation by the catalytic acid and the charge-dipole interaction with the catalytic nucleophile contribute cooperatively to the binding of inhibitors possessing a trigonal anomeric centre bonded to a heteroatom.
Additional Material:
5 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/hlca.19980810507
