You have been tasked with designing new inhibitors for a Ser

You have been tasked with designing new inhibitors for a Ser process as possible leads for drug design. What structural features would you consider important in designing a transition state analog inhibitor and a mechanism-based inhibitor? Discuss both types of inhibitors. For your assistance, a schematic of the active site for chymotrypsin is provided.

Solution

Ans.) Basically, serine protease is an enzymes that cut the peptide bond in protein, in this process serine serve as the nucleophilic amino acid at the active site of the enzyme. They are found universally in both eukaryotes and prokaryotes. They are responsible for coordinating various physiological functions, including digestion, immune response, blood coagulation and reproduction.

The important structural feature must be present in such inhibitor are two beta-barrel domains that converge at the catalytic active site and a substrate specificity as either trypsin-like, chymotrypsin-like or elastase-like.

There are several inhibitor found in chemical reactions.

Transition state analog inhibitor – They structurally similar to transition state which binds even more tightly to enzyme than substrate binds, so very high affinity for active site.

Transition state analog used for understanding catalytic mechanism and also as specific inhibitor of enzymes used in pharmaceutical application. They are also used as antigens for immunizing lab animals to generate antibodies with binding sites complementary to the transition state such that the antibodies themselves have catalytic activity that is abzymes.

Mechanism-based inhibitor – They are structurally similar to substrate and act as guide reagent to active site. Enzyme treats it as a substrate and starts the chemical catalytic process with inhibitor. Chemical mechanism itself leads enzyme to react covalently with inhibitor, thus killing itself. Mechanism-based inhibition depends on chemical mechanism of catalysis.