4DP3

Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P218 and NADPH

4DP3 の概要

• エントリーDOI: 10.2210/pdb4dp3/pdb
• 関連するPDBエントリー: 1J3K 2JSU 3QG2 4DDR 4DPD 4DPH
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: rossmann fold, reductase, oxidoreductase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Plasmodium falciparum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 146217.87

構造登録者

Yuthavong, Y.,Vilaivan, T.,Kamchonwongpaisan, S.,Charman, S.A.,McLennan, D.N.,White, K.L.,Vivas, L.,Bongard, E.,Chitnumsub, P.,Tarnchompoo, B.,Thongphanchang, C.,Taweechai, S.,Vanichtanakul, J.,Arwon, U.,Fantauzzi, P.,Yuvaniyama, J.,Charman, W.N.,Matthews, D. (登録日: 2012-02-13, 公開日: 2012-11-14, 最終更新日: 2023-11-08)

主引用文献

Yuthavong, Y.,Tarnchompoo, B.,Vilaivan, T.,Chitnumsub, P.,Kamchonwongpaisan, S.,Charman, S.A.,McLennan, D.N.,White, K.L.,Vivas, L.,Bongard, E.,Thongphanchang, C.,Taweechai, S.,Vanichtanankul, J.,Rattanajak, R.,Arwon, U.,Fantauzzi, P.,Yuvaniyama, J.,Charman, W.N.,Matthews, D.
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
Proc.Natl.Acad.Sci.USA, 109:16823-16828, 2012

PubMed Abstract: Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.

PubMed: 23035243
DOI: 10.1073/pnas.1204556109

実験手法

X-RAY DIFFRACTION (2.4 Å)