6A7E

Human dihydrofolate reductase complexed with NADPH and BT2

Summary for 6A7E

• Entry DOI: 10.2210/pdb6a7e/pdb
• Related: 6A7C
• Descriptor: Dihydrofolate reductase, 5-(4-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)-6-ethylpyrimidine-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: dhfr, antifolate, inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22519.44

Authors

Vanichtanankul, J.,Tarnchompoo, B.,Chitnumsub, P.,Kamchonwongpaisan, S.,Yuthavong, Y. (deposition date: 2018-07-02, release date: 2019-04-10, Last modification date: 2023-11-22)

Primary citation

Tarnchompoo, B.,Chitnumsub, P.,Jaruwat, A.,Shaw, P.J.,Vanichtanankul, J.,Poen, S.,Rattanajak, R.,Wongsombat, C.,Tonsomboon, A.,Decharuangsilp, S.,Anukunwithaya, T.,Arwon, U.,Kamchonwongpaisan, S.,Yuthavong, Y.
Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.
ACS Med Chem Lett, 9:1235-1240, 2018

PubMed Abstract: The S108N mutation of dihydrofolate reductase (DHFR) renders malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.

PubMed: 30613332
DOI: 10.1021/acsmedchemlett.8b00389

Experimental method

X-RAY DIFFRACTION (1.85 Å)