Summary for 9KP9
| Entry DOI | 10.2210/pdb9kp9/pdb |
| Related | 8ZXX |
| Descriptor | 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, MANGANESE (II) ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, malaria, isomerase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 1 |
| Total formula weight | 57021.39 |
| Authors | |
| Primary citation | Knak, T.,Takada, S.,Illarionov, B.,Krisilia, V.,Pessanha de Carvalho, L.,Lungerich, B.,Sakamoto, Y.,Hofmann, S.,Bacher, A.,Kalscheuer, R.,Held, J.,Fischer, M.,Tanaka, N.,Kurz, T. Expanding the Chemical Space of Reverse Fosmidomycin Analogs. Acs Med.Chem.Lett., 16:136-143, 2025 Cited by PubMed Abstract: Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for , , and that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no growth inhibition of the pathogens. Crystallographic studies revealed that compounds and induce an open DXR conformation and that the enzyme selectively binds the -enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies. PubMed: 39811140DOI: 10.1021/acsmedchemlett.4c00501 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.13 Å) |
Structure validation
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