UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date


Document Type

Article Postprint


Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry


Protein Arginine Deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, multiple sclerosis, lupus, and certain cancers. These pathologies established the PADs as therapeutic targets and multiple PAD inhibitors are known. Herein, we describe the first highly potent PAD1-selective inhibitors (1 and 19). Detailed structure-activity relationships indicate that their potency and selectivity is due to the formation of a halogen bond with PAD1. Importantly, these inhibitors inhibit histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes with excellent potency. Based on this scaffold, we also developed a PAD1-selective activity-based probe that shows remarkable cellular efficacy and proteome selectivity. Based on their potency and selectivity we expect that 1 and 19 will be widely used chemical tools to understand PAD1 biology.


Activity-based protein profiling, Covalent protein modification, Halogen Bonding, Histone citrullination, Protein arginine deiminase

Rights and Permissions

© 2019 WILEY‐VCH Verlag GmbH. This is the peer reviewed version of the following article: Mondal, S. , Gong, X. , Zhang, X. , Salinger, A. ., Zheng, L. , Sen, S. , Weerapana, E. , Zhang, X. and Thompson, P. (2019), Halogen Bonding Increases the Potency and Isozyme‐selectivity of Protein Arginine Deiminase 1 Inhibitors. Angew. Chem. Int. Ed. doi:10.1002/anie.201906334, which has been published in final form at First published 05 July 2019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions,

DOI of Published Version



Mondal S, Gong X, Zhang X, Salinger AJ, Zheng L, Sen S, Weerapana E, Zhang X, Thompson PR. Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors. Angew Chem Int Ed Engl. 2019 Sep 2;58(36):12476-12480. doi: 10.1002/anie.201906334. Epub 2019 Jul 5. PMID: 31276611; PMCID: PMC6713606. Link to article on publisher's website

Journal/Book/Conference Title

Angewandte Chemie (International ed. in English)

Related Resources

Link to article in PubMed

PubMed ID


Mondal et al 2019 Supporting information ver 6.pdf (7766 kB)
Supporting information

TOC.tif (2898 kB)
Figure for Table of Contents



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