Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors.

Journal of medicinal chemistry 2017 Mar 09

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Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.

Citation

Anna Vulpetti, Stefan Randl, Simon Rüdisser, Nils Ostermann, Paul Erbel, Aengus Mac Sweeney, Thomas Zoller, Bahaa Salem, Bernd Gerhartz, Frederic Cumin, Ulrich Hommel, Claudio Dalvit, Edwige Lorthiois, Jürgen Maibaum. Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors. Journal of medicinal chemistry. 2017 Mar 09;60(5):1946-1958