8WGN
Human dihydrofolate reductase (HsDHFR) complexed with NADPH and LA1
Summary for 8WGN
| Entry DOI | 10.2210/pdb8wgn/pdb |
| Descriptor | Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (3~{E})-3-[[2-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]oxypropoxy]phenyl]methylidene]oxolan-2-one, ... (5 entities in total) |
| Functional Keywords | antifolate, inhibitor, dhfr, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 22994.83 |
| Authors | Vanichtanankul, J.,Saeyang, T.,Vitsupakorn, D.,Decharuangsilp, S.,Arwon, U.,Yuthavong, Y.,Kamchonwongpaisan, S. (deposition date: 2023-09-22, release date: 2024-09-11, Last modification date: 2024-09-25) |
| Primary citation | Decharuangsilp, S.,Arwon, U.,Hoarau, M.,Vanichtanankul, J.,Saeyang, T.,Jantra, T.,Rattanajak, R.,Thiabma, R.,Sooksai, N.,Kongkasuriyachai, D.,Kamchonwongpaisan, S.,Yuthavong, Y. Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors. Bioorg.Chem., 153:107789-107789, 2024 Cited by PubMed Abstract: Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates. PubMed: 39250850DOI: 10.1016/j.bioorg.2024.107789 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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