4IGE

Crystal structure of Plasmodium falciparum FabI complexed with NAD and inhibitor 7-(4-Chloro-2-hydroxyphenoxy)-4-methyl-2H-chromen-2-one

Summary for 4IGE

• Entry DOI: 10.2210/pdb4ige/pdb
• Related: 4IGF
• Descriptor: Enoyl-acyl carrier reductase, 7-(4-chloro-2-hydroxyphenoxy)-4-methyl-2H-chromen-2-one, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 81031.29

Authors

Kostrewa, D.,Perozzo, R. (deposition date: 2012-12-17, release date: 2013-11-06, Last modification date: 2023-11-08)

Primary citation

Belluti, F.,Perozzo, R.,Lauciello, L.,Colizzi, F.,Kostrewa, D.,Bisi, A.,Gobbi, S.,Rampa, A.,Bolognesi, M.L.,Recanatini, M.,Brun, R.,Scapozza, L.,Cavalli, A.
Design, Synthesis, and Biological and Crystallographic Evaluation of Novel Inhibitors of Plasmodium falciparum Enoyl-ACP-reductase (PfFabI)
J.Med.Chem., 56:7516-7526, 2013

PubMed Abstract: Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.

PubMed: 24063369
DOI: 10.1021/jm400637m

Experimental method

X-RAY DIFFRACTION (2.15 Å)