6KOT

Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with B12128 and NADPH

Summary for 6KOT

• Entry DOI: 10.2210/pdb6kot/pdb
• Descriptor: Bifunctional dihydrofolate reductase-thymidylate synthase, 4-[3-[[2,6-bis(azanyl)-5-(3-chlorophenyl)pyrimidin-4-yl]methoxy]phenoxy]butanoic acid, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: quadruple mutant dihydrofolate reductase, inhibitor, plasmodium falciparum, oxidoreductase, transferase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 2
• Total formula weight: 146781.21

Authors

Vanichtanankul, J.,Vitsupakorn, D. (deposition date: 2019-08-13, release date: 2019-12-04, Last modification date: 2023-11-22)

Primary citation

Saepua, S.,Sadorn, K.,Vanichtanankul, J.,Anukunwithaya, T.,Rattanajak, R.,Vitsupakorn, D.,Kamchonwongpaisan, S.,Yuthavong, Y.,Thongpanchang, C.
6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.
Bioorg.Med.Chem., 27:115158-115158, 2019

PubMed Abstract: The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122.

PubMed: 31685330
DOI: 10.1016/j.bmc.2019.115158

Experimental method

X-RAY DIFFRACTION (2.149 Å)