5NAR
Complement factor D in complex with the inhibitor (S)-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]
Summary for 5NAR
| Entry DOI | 10.2210/pdb5nar/pdb |
| Descriptor | Complement factor D, SULFATE ION, (2~{S})-~{N}1-(1-aminocarbonylindol-3-yl)-~{N}2-[3-(trifluoromethyloxy)phenyl]pyrrolidine-1,2-dicarboxamide, ... (4 entities in total) |
| Functional Keywords | hydrolase |
| Biological source | Homo sapiens (Human) |
| Cellular location | Secreted: P00746 |
| Total number of polymer chains | 1 |
| Total formula weight | 25310.60 |
| Authors | Mac Sweeney, A.,Ostermann, N. (deposition date: 2017-02-28, release date: 2017-06-28, Last modification date: 2024-11-13) |
| Primary citation | Lorthiois, E.,Anderson, K.,Vulpetti, A.,Rogel, O.,Cumin, F.,Ostermann, N.,Steinbacher, S.,Mac Sweeney, A.,Delgado, O.,Liao, S.M.,Randl, S.,Rudisser, S.,Dussauge, S.,Fettis, K.,Kieffer, L.,de Erkenez, A.,Yang, L.,Hartwieg, C.,Argikar, U.A.,La Bonte, L.R.,Newton, R.,Kansara, V.,Flohr, S.,Hommel, U.,Jaffee, B.,Maibaum, J. Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. J. Med. Chem., 60:5717-5735, 2017 Cited by PubMed Abstract: The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD. PubMed: 28621538DOI: 10.1021/acs.jmedchem.7b00425 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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