Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist.

ABSTRACT: Examination of a series of naturally-occurring trypsin inhibitor proteins, led to identification of a set of three residues (which we call the "interface triplet") to be determinant of trypsin binding affinity, hence excellent templates for small molecule mimicry. Consequently, we attempted to use the Exploring Key Orientation (EKO) strategy developed in our lab to evaluate small molecules that mimic the interface triplet regions of natural trypsin inhibitors, and hence potentially might bind and inhibit the catalytic activity of trypsin. A bis-triazole scaffold ("TT-mer") was the most promising of the molecules evaluated in silico. Twelve such compounds were synthesized and assayed against trypsin, among which the best showed a K_d of 2.1 μM. X-ray crystallography

SUBMITTER: Lyu RL 

PROVIDER: S-EPMC10365224 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature