258 2. ANALOGS OF ENZYME REACTION COMPONENTS 



determined so that modifications in the structure may be made in the proper 

 regions. The examjjles discussed in this chapter will clearly demonstrate 

 that many analog inhibitors are not isosteric or isomorphic with the sub- 

 strate and that, indeed, many of the most useful inhibitors appear to dif- 

 fer quite markedly from the substrate. In this connection it is necessary 

 to call attention to the danger of visualizing molecules on the basis of their 

 classic two-dimensional formulas. One must also realize that usually not 

 all of a substrate molecule is involved in the binding and reaction with the 

 enzyme; the side of the molecule more distant from the enzyme may be 

 relatively less important than the rest of the molecule and modifications 

 on this side may give the appearance of producing radically different sub- 

 stances, whereas from the standpoint of the enzyme surface these sub- 

 stances may be very similar to the substrate. Conversely, just because two 

 substances look alike when written in the usual structural formulas is not 

 enough to ensure that they will exhibit comparable interactions with the 

 active center of an enzyme. Ideally, one should learn to conceive enzyme 

 reactions on an electronic and molecular level and to visualize analogs 

 with three-dimensional molecular imagination, in other words, to approach 

 the problem of analog design from the point of view of a rational active 

 center. 



Some analogs are not directly inhibitory but are metabolically trans- 

 formed into inhibitory substances that block a sequence at a later step. 

 Such analogs are often very interesting and useful, being in many cases 

 specific and potent. The design of an analog to be an inhibitor precursor 

 presents a slightly different problem than in the general case. If the analog 

 is to enter into the metabolic sequence it must be a substrate of the initial 

 enzymes and, hence, structurally similar to the natural substrate in the 

 region of the reactive groups. Isosteric and isomorphic substitution is often 

 useful in this situation. This probably accounts for the popularity of fluo- 

 rine as a replacement for a H atom in the design of this type of analog. 

 Many F-substituted analogs enter into metabolic sequences and interfere 

 at a more distal region, for example, fluoroacetate, 5-fluorouracil, 2>-fluoro- 

 phenylalanine, and 6-deoxy-6-fluoro-D-glucose. The F atom is the smallest 

 of the common atoms that may be substituted for a H atom, and approaches 

 the H atom in size (van der Waals' radii for H and F atoms being 1.2 and 

 1.35 A, respectively) (see Table 1-6-8). The F atom is also relatively un- 

 reactive and forms a stable bond to carbon. However, it is strongly electro- 

 negative and alters the electronic configuration in comparison to the parent 

 compound. The dipole moment of the C — F bond will be quite different 

 from the C — H bond, this altering neighboring bonds as well as inducing 

 an ability to form hydrogen bonds with the enzyme. Thus the F analog 

 not only may be much like the substrate in over all size and configuration, 

 allowing it to be metabolically reactive, but eventually may be transformed 



