Enzyme inhibitiors: Ground‐state/transition‐state analogs

Compactin and related compounds are highly effective inhibitors of HMG‐CoA (Hydroxymethylglutaryl‐CoA) reductase. These compounds consist of two major structural components: (1) a component resembling hydroxymethyl glutarate and (2) a hydrophobic region. It is concluded that the hydroxymethyl glutarate moiety of these inhibitors interacts with the hydroxymethyl glutarate‐binding domain of the active site. It is postulated that the hydrophobic moiety of these inhibitors interacts with a hydrophobic area of the enzyme that is not part of the active site. Strong binding is the consequence of this two‐point interation. Peptidyl tri‐fluoroketones are effective inhibitors of chymotrypsin and elastase and are probably transition‐state analogs. These inhibitors form an adduct with the activesite serine as determined by X‐ray crystallography and nuclear magnetic resonance spectroscopy. Maximum inhibition is obtained if inhibitors interact with the S and S′ binding domains. The structure of ovomucoids, protein inhibitors of serine proteases, serves as a good model for the determination of the amino acid sequence to be used in that portion of the inhibitor which interacts with the S′ domain. The best amino‐acid sequence to be used in that area of the inhibitor which interacts with the S‐binding domain corresponds to the amino‐acid sequence found in substrates with the highest V/K.