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. 2025 Jul 9;16(8):1662-1669.
doi: 10.1021/acsmedchemlett.5c00372. eCollection 2025 Aug 14.

Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule

Mark E Schnute  1 , Gary M Chinigo  2 , Kentaro Futatsugi  1 , Masaya Yamaguchi  2 , Scott W Bagley  2 , Mary Ellen Banker  2 , Jeanne S Chang  2 , Ming Z Chen  2 , Won Young Choi  2 , Matthew S Corbett  2 , Susan E Drozda  2 , David C Ebner  1 , Carmen Garcia-Irizarry  2 , Robert Hicklin  2 , Susan Hoy  2 , Wenhua Jiao  2 , Steven Kortum  2 , Katherine L Lee  1 , David C Limburg  2 , Frank Lovering  1 , Antonio Moreno  2 , James J Mousseau  2 , Senliang Pan  2 , Mihir D Parikh  2 , Jeffrey W Pelker  3 , Simeon Ramsey  3 , Usa Reilly  2 , Gwenaella Rescourio  1 , Daniel C Schmitt  2 , Brittany Simpson  2 , Grzegorz J Skrzypek  2 , Daniel J Smaltz  1 , Alexandria P Taylor  2 , Rubben Torella  1 , John I Trujillo  2 , Felix F Vajdos  2 , James A Wepy  1 , Stephen W Wright  2 , David C Blakemore  2 , Fabien Vincent  2 , Valerie M Clerin  3
Affiliations

Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule

Mark E Schnute et al. ACS Med Chem Lett. .

Abstract

Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1-4), and inhibition of one or several PAD isozymes in combination may offer a therapeutic approach to targeting these diseases. Building upon the discovery of PAD-PF2, an allosteric inhibitor of PAD1-4, herein, we report on the optimization of potency and pharmacokinetic properties while minimizing hERG channel liabilities within this novel chemical series. Through structure-based ligand design, a structural water was successfully displaced, allowing expansion of the ligand binding site and access to a previously unexplored hydrophobic pocket resulting in a 10-fold improvement in potency. Compound 4f demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species.

Keywords: PADI2; PADI4; allosteric binding site; citrullination; peptidylarginine deiminases; water molecule displacement.

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