IMPORTANT TYPES OF MOLECULAR ALTERATION 257 



This is known to occur in the case of diisopropylfluorophosphate and re- 

 lated cholinesterase inhibitors, as well as with monoamine oxidase inhibi- 

 tors such as iproniazid. 



An analog may be related to the corresponding substrate in one of two 

 general ways: it may be either an isomer of tne substrate, or a substance 

 obtained by the replacement of one or more groups on the substrate. 

 An isomeric analog may be a geometric isomer (e.g., one of a cis and trans 

 pair), optical isomer, or any stereoisomer of the substrate. It might be 

 thought that such analogs would often be specific and useful inhibitors but 

 actually, except for certain optical isomers (see page 268), this is seldom 

 the case, the reason being that the configuration of the analog is more 

 important than a simple equivalence of all the atoms and groups. A sub- 

 stitution analog can result from a variety of molecular changes in the sub- 

 strate. What is often called addition of groups is usually only a substitution 

 of the new group for a H atom (e.g., the replacement of a H atom with a 

 F atom or a CH3 group), and what is called deletion of groups is usually 

 a substitution of a H atom for the group that is removed. On the other hand, 

 an important type of analog is derived by the substitution of one functional 

 group with another group (e.g., the replacement of an OH group with a 

 SH group, or of a CH3 group with a CI atom). Some commonly interchangea- 

 ble groups might be put in the following families: 



(a) — NH2 —OH — SH — CH3 —CI — F — H 



(b) —COO- — SO3- — ASO3H- — PO3- 



(c) — CONH2 — SO2NH2 



{d) — S— —0— — NH— — CH=CH— — CH2— 



(e) — Phenyl — benzyl — pyridyl — pyrimidyl — cyclohexyl 



A good deal has been written about isosteric and isomorphic groups in the 

 production of analogs (for an excellent review see Schatz, 1960), especially 

 with respect to the development of new drugs, but this has limited bearing 

 on the elaboration of enzyme inhibitors. The replacement of substrate 

 groups with isosteric and approximately isomorphic groups usually leads 

 to substances that are also substrates. It is generally necessary to alter 

 the proper region of the substrate molecule significantly in order to produce 

 an effective inhibitor. There are actually at the present time no general 

 rules for the most efficient procedures to be used for the modification of 

 substrates to produce inhibitors. Various enzymes exhibit quite different 

 reaction mechanisms and an effective transformation of the substrate in 

 one case will not work for other enzymes. For this reason the most important 

 thing to establish initially is the nature of the particular enzyme mechanism, 

 if an attempt is to be made to design analogs rationally. The binding groups, 

 reactive groups, and relatively neutral groups in the substrate must be 



