Question

You are designing a drug that inhibits a metalloprotease and is based on the structure of its natural peptide substrate. Select all that apply

A tetrahedral carbon with a single alcohol group replacing the carbonyl carbon at the scissile bond is one of the best strategies for designing an inhibitor because:

1.The shape matches that of the transition state

2.It is roughly isoelectronic with the transition state

3.It is hard to hydrolyze

4.It is not charged and therefore more likely to be orally bioavailable

5.It replaces the zinc ions in the active site

6.It makes a covalent intermediate with and active-site serine side chain

Answer 1

The reason is the tetrahedral shape of the alcohol that attacks the scissile carbonyl bond. The transition state is tetrahedral. The alcohol adds to the planer carbonyl group and therefore, in the transition state, four groups are disposed around the carbonyl carbon. A carbon atom with four substituents assumes a tetrahedral geometry and hence the transition state is tetrahedral. Therefore, the answer is (1).