8YQ9
Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS V1/S) complexed with FB6, NADPH and dUMP
This is a non-PDB format compatible entry.
Summary for 8YQ9
| Entry DOI | 10.2210/pdb8yq9/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[4-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]oxypropoxy]phenyl]benzoic acid, ... (6 entities in total) |
| Functional Keywords | dihydrofolate reductase, thymidylate synthase, antifolate, plasmodium falciparum, biphenyl, fragment, oxidoreductase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 2 |
| Total formula weight | 146924.56 |
| Authors | Vanichtanankul, J.,Vitsupakorn, D.,Saeyang, T.,Arwon, U.,Hoarau, M.,Decharuangsilp, S.,Kamchonwongpaisan, S.,Yuthavong, Y. (deposition date: 2024-03-19, release date: 2024-09-11) |
| Primary citation | Decharuangsilp, S.,Arwon, U.,Sooksai, N.,Rattanajak, R.,Saeyang, T.,Vitsupakorn, D.,Vanichtanankul, J.,Yuthavong, Y.,Kamchonwongpaisan, S.,Hoarau, M. Novel flexible biphenyl Pf DHFR inhibitors with improved antimalarial activity. Rsc Med Chem, 15:2496-2507, 2024 Cited by PubMed Abstract: As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl DHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design. PubMed: 39026651DOI: 10.1039/d4md00197d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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