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Publication Abstract from PubMed

Complement Factor D, a serine protease of the S1 family and key component of the alternative pathway amplification loop, represents a promising target for the treatment of several prevalent and rare diseases linked to the innate immune system. Previously reported FD inhibitors have been shown to bind to the FD active site in its self-inhibited conformation characterized by the presence of a salt bridge at the bottom of the S1 pocket between Asp189 and Arg218. We report herein a new set of small-molecule FD ligands that harbor a basic S1 binding moiety directly binding to the carboxylate of Asp189, thereby displacing the Asp189-Arg218 ionic interaction and significantly changing the conformation of the self-inhibitory loop.

Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D.,Vulpetti A, Ostermann N, Randl S, Yoon T, Mac Sweeney A, Cumin F, Lorthiois E, Rudisser S, Erbel P, Maibaum J ACS Med Chem Lett. 2018 Apr 24;9(5):490-495. doi: 10.1021/acsmedchemlett.8b00104., eCollection 2018 May 10. PMID:29795765^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.