Issue 10, 2022

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 Kd of 2.1 μM. X-ray crystallography revealed a high degree of matching between an illustrative TT-mer's actual binding mode and that of the mimics that overlaid the interface triplet in the crystal structure. Deviation of the third side chain from the PPI structure seems to be due to alleviation of an unfavorable dipole–dipole interaction in the small molecule's actual bound conformation.

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

Supplementary files

Article information

Article type
Communication
Submitted
29 Here 2021
Accepted
25 Du 2021
First published
09 Ker. 2021

Org. Biomol. Chem., 2022,20, 2075-2080

Author version available

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

R. Lyu, S. Joy, C. Packianathan, A. Laganowsky and K. Burgess, Org. Biomol. Chem., 2022, 20, 2075 DOI: 10.1039/D1OB02127C

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