Enzyme structure-activity studies

T. Fujita and T. Ban, Structure-activity study of phenethylamines as substrates of biosynthetic enzymes of sympathetic transmitters. J. Med. Chem., 14 (1971) 148-152. 

Mayer, D., Naylor, C.B., Motoc, I., Marshall, G.R. Aunique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies./. Comput.-Aided Mol. Des. 1987, 3(1), 3-16. 

In 1995, Silverman and Hawe published structure-activity studies of fluorine-substituted benzylamines and substituted 2-phenylethylamines. Introduction of one or several fluorine atoms makes these compounds good substrates for MAO B (see Table 1), but none of them was an inactivator of the enzyme [31],... 

Although the toxicity of the vast majority of heterocyclic compounds remains unknown, a few have been studied in detail, usually because a mechanistically interesting or useful toxicity is involved. It would obviously have been inappropriate to devote the whole of this chapter to these agents simply because they have been studied, but consideration at this point of some of them will illustrate many of the general principles discussed earlier — in particular, that toxicity is usually apparent within a family of nominally related chemicals and that the relative activity of individual members may provide information on the physiological or molecular basis of the toxic effect. Sections 1.05.3.6.3-1.05.3.6.5 below are particularly concerned with heterocycles that affect enzyme function. We have selected these firstly because many toxins require enzyme-mediated conversion to an active species, and secondly because many detailed structure-activity studies are available for such agents. 

The prerequisite for protein engineering studies is that the enzyme has been cloned and expressed. Further, unless only relatively crude information is required, it is essential that the structure has been solved at high resolution. Accurate structure-activity studies require even more stringent criteria absolute values of rate constants. The two following procedures, which were discussed earlier (Chapter 4, section E), must be available. Both depend on the accumulation of an enzyme-bound intermediate or product on the reaction pathway. 

Fujita, T. and Ban, T. (1971). Structure-Activity Study of Phenethylamines as Substrates of Biosynthetic Enzymes of Sympathetic Transmitters. J.Med.Chem., 14,148-152. 

C. Hansch and E. Coats, a-Chymotrypsin A Case Study of Substituent Constants and Regression Analysis in Enzymic Structure-Activity Relationships, J. Pharm. Sci., 1970, 59, 731. 

Pharmacophoric patterns have been proposed as the result of structure-activity studies, modeling studies, mechanistic studies, and enzyme structural studies. While two atom ("distance") and three atom ("triangle") pharmacophoric patterns have been proposed, we would not expect these to be as discriminating as more detailed patterns. Proposed pharmacophoric patterns have been reviewed by Kler,9 Korolkovas,10 and Gund.7 Some additional proposed patterns of drug pharmacophores and of complementary receptor maps are listed in Table I. 

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