Summary for 9OVQ
| Entry DOI | 10.2210/pdb9ovq/pdb |
| Descriptor | Protein-arginine deiminase type-2, (2S)-2-amino-2-(1-{(5M)-5-[3,5-dichloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl]isoquinolin-1-yl}piperidin-4-yl)-N-methylacetamide, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | deiminase, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 77608.87 |
| Authors | Yamaguchi, M. (deposition date: 2025-05-30, release date: 2025-07-30, Last modification date: 2025-09-03) |
| Primary citation | Schnute, M.E.,Chinigo, G.M.,Futatsugi, K.,Yamaguchi, M.,Bagley, S.W.,Banker, M.E.,Chang, J.S.,Chen, M.Z.,Choi, W.Y.,Corbett, M.S.,Drozda, S.E.,Ebner, D.C.,Garcia-Irizarry, C.,Hicklin, R.,Hoy, S.,Jiao, W.,Kortum, S.,Lee, K.L.,Limburg, D.C.,Lovering, F.,Moreno, A.,Mousseau, J.J.,Pan, S.,Parikh, M.D.,Pelker, J.W.,Ramsey, S.,Reilly, U.,Rescourio, G.,Schmitt, D.C.,Simpson, B.,Skrzypek, G.J.,Smaltz, D.J.,Taylor, A.P.,Torella, R.,Trujillo, J.I.,Vajdos, F.F.,Wepy, J.A.,Wright, S.W.,Blakemore, D.C.,Vincent, F.,Clerin, V.M. Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule. Acs Med.Chem.Lett., 16:1662-1669, 2025 Cited by PubMed 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 demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species. PubMed: 40832545DOI: 10.1021/acsmedchemlett.5c00372 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.175 Å) |
Structure validation
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