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 lis 2021
Accepted
25 stu 2021
First published
09 pro 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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements