Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors
| Autor: | Paul Erbel, Bernd Gerhartz, Frederic Cumin, Jürgen Maibaum, Nils Ostermann, Edwige Lorthiois, Claudio Dalvit, Thomas Zoller, Stefan Andreas Randl, Simon Rüdisser, Ulrich Hommel, Anna Vulpetti, Aengus Mac Sweeney, Bahaa Salem |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Magnetic Resonance Spectroscopy In silico medicine.medical_treatment 010402 general chemistry 01 natural sciences 03 medical and health sciences Catalytic Domain Complement Factor D Drug Discovery Hydrolase medicine Humans Protease Inhibitors Serine protease Protease Molecular Structure biology Chemistry 0104 chemical sciences Complement system 030104 developmental biology Biochemistry Drug Design biology.protein Alternative complement pathway Molecular Medicine Factor D |
| Zdroj: | Journal of Medicinal Chemistry. 60:1946-1958 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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