8JFC
V1/S quadruple mutant Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 6 (B21591), NADPH and dUMP
Summary for 8JFC
| Entry DOI | 10.2210/pdb8jfc/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, ... (6 entities in total) |
| Functional Keywords | dhfr, dihydrofolate reductase, plasmodium falciparum, malaria, oxidoreductase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 2 |
| Total formula weight | 146804.46 |
| Authors | Vanichtanankul, J.,Saeyang, T.,Vitsupakorn, D.,Saepua, S.,Thongpanchang, C.,Yuthavong, Y.,Kamchonwongpaisan, S.,Hoarau, M. (deposition date: 2023-05-17, release date: 2023-08-23, Last modification date: 2023-10-04) |
| Primary citation | Hoarau, M.,Sermmai, P.,Varatthan, T.,Thiabma, R.,Jantra, T.,Rattanajak, R.,Vitsupakorn, D.,Vanichtanankul, J.,Saepua, S.,Yuthavong, Y.,Thongpanchang, C.,Kamchonwongpaisan, S. Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy. Rsc Med Chem, 14:1755-1766, 2023 Cited by PubMed Abstract: dihydrofolate reductase (DHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine () overexposure. The clinical candidate has demonstrated that inhibitors could efficiently target both -sensitive and -resistant parasites through careful drug design. Yet, clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen. Herein, we report the design of new DHFR inhibitors using fragment-based design, aiming at improved lipophilicity and overall drug-like properties. Fragment-based screening identified hits binding in the pABA site of the enzyme. Using structure-guided design, hits were elaborated into leads by fragment linking with 2,4-diaminopyrimidine. Resulting compounds display nM range inhibition of both drug-sensitive and resistant DHFR, high selectivity against the human isoform, drug-like lipophilicity and metabolic stability. Compound 4 and its ester derivative 3 kill blood stage TM4/8.2 parasite at nM concentrations while showing no toxicity against Vero cells. PubMed: 37731689DOI: 10.1039/d3md00242j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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