Investigation of the Compatibility Between Warheads and Peptidomimetic Sequences of Protease Inhibitors-A Comprehensive Reactivity and Selectivity Study

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Apr 28

PMID 37108388

Authors

Patrick Muller

Mergim Meta

Jan Laurenz Meidner

Marvin Schwickert

Jessica Meyr

Kevin Schwickert

Christian Kersten

Collin Zimmer

Stefan Josef Hammerschmidt

Ariane Frey

Albin Lahu

Sergio de la Hoz-Rodriguez

Laura Agost-Beltran

Santiago Rodriguez

Kira Diemer

Wilhelm Neumann

Florenci V Gonzalez

Bernd Engels

Tanja Schirmeister

Affiliations

Soon will be listed here.

Abstract

Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations.

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