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Structure-based library design and fragment-based screening for the identification of novel Factor D inhibitors

Vulpetti, Anna and Ruedisser, Simon and Ostermann, Nils and Erbel, Paulus and Zoller, Thomas and Salem, Bahaa and Gerhartz, Bernd and Hommel, Ulrich and Lorthiois, Edwige and Maibaum, Juergen Klaus (2017) Structure-based library design and fragment-based screening for the identification of novel Factor D inhibitors. Journal of medicinal chemistry.

Abstract

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 catalyses the first enzymatic reaction of the amplification loop of the alternative pathway. In this paper, 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 spots identification to guide rational structure-based design and NMR screening of focussed and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different sub-pockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent non-covalent reversible Factor D inhibitors.

Item Type: Article
Keywords: Alternative Complement Pathway, Factor D inhibitors, Fragment Based Screening, Structure Based Drug Design, NMR
Date Deposited: 18 Feb 2017 00:45
Last Modified: 18 Feb 2017 00:45
URI: https://oak.novartis.com/id/eprint/31083

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