3DG8

Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with RJF670, NADPH, and dUMP

3DG8 の概要

• エントリーDOI: 10.2210/pdb3dg8/pdb
• 関連するPDBエントリー: 1J3I 1J3J 1J3K 3DGA
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, N-(3,5-dimethoxyphenyl)imidodicarbonimidic diamide, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• 機能のキーワード: alpha-beta, methyltransferase, oxidoreductase, transferase
• 由来する生物種: Plasmodium falciparum; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 146434.24

構造登録者

Dasgupta, T.,Chitnumsub, P.,Maneeruttanarungroj, C.,Kamchonwongpaisan, S.,Nichols, S.,Lyons, T.M.,Tirado-Rives, J.,Jorgensen, W.L.,Yuthavong, Y.,Anderson, K.S. (登録日: 2008-06-13, 公開日: 2009-01-27, 最終更新日: 2023-08-30)

主引用文献

Dasgupta, T.,Chitnumsub, P.,Kamchonwongpaisan, S.,Maneeruttanarungroj, C.,Nichols, S.E.,Lyons, T.M.,Tirado-Rives, J.,Jorgensen, W.L.,Yuthavong, Y.,Anderson, K.S.
Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria.
Acs Chem.Biol., 4:29-40, 2009

PubMed Abstract: Plasmodium falciparum thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in folate biosynthesis and a major malarial drug target. This bifunctional enzyme thus presents different design approaches for developing novel inhibitors against drug-resistant mutants. We performed a high-throughput in silico screen of a database of diverse, drug-like molecules against a non-active-site pocket of TS-DHFR. The top compounds from this virtual screen were evaluated by in vitro enzymatic and cellular culture studies. Three compounds active to 20 microM IC(50)'s in both wildtype and antifolate-resistant P. falciparum parasites were identified; moreover, no inhibition of human DHFR enzyme was observed, indicating that the inhibitory effects appeared to be parasite-specific. Notably, all three compounds had a biguanide scaffold. However, relative free energy of binding calculations suggested that the compounds might preferentially interact with the active site over the screened non-active-site region. To resolve the two possible modes of binding, co-crystallization studies of the compounds complexed with TS-DHFR enzyme were performed. Surprisingly, the structural analysis revealed that these novel, biguanide compounds do indeed bind at the active site of DHFR and additionally revealed the molecular basis by which they overcome drug resistance. To our knowledge, these are the first co-crystal structures of novel, biguanide, non-WR99210 compounds that are active against folate-resistant malaria parasites in cell culture.

PubMed: 19146480
DOI: 10.1021/cb8002804

実験手法

X-RAY DIFFRACTION (2.58 Å)