3H4V

Selective screening and design to identify inhibitors of leishmania major pteridine reductase 1

「2P8K」から置き換えられました

3H4V の概要

• エントリーDOI: 10.2210/pdb3h4v/pdb
• 関連するPDBエントリー: 1e92 1p33 1w0c 2bf7 2bfa 2bfm 2qhx
• 分子名称: Pteridine reductase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, METHYL 1-(4-{[(2,4-DIAMINOPTERIDIN-6-YL)METHYL]AMINO}BENZOYL)PIPERIDINE-4-CARBOXYLATE, ... (4 entities in total)
• 機能のキーワード: short-chain reductase, leishmania, trypanosoma, ptr1, inhibitor, oxidoreductase, methotrexate resistance, nadp
• 由来する生物種: Leishmania major
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 252963.62

構造登録者

Mcluskey, K.,Gibellini, F.,Hunter, W.N. (登録日: 2009-04-21, 公開日: 2009-05-05, 最終更新日: 2023-11-01)

主引用文献

Cavazzuti, A.,Paglietti, G.,Hunter, W.N.,Gamarro, F.,Piras, S.,Loriga, M.,Allecca, S.,Corona, P.,McLuskey, K.,Tulloch, L.,Gibellini, F.,Ferrari, S.,Costi, M.P.
Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development
Proc.Natl.Acad.Sci.USA, 105:1448-1453, 2008

PubMed Abstract: Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.

PubMed: 18245389
DOI: 10.1073/pnas.0704384105

実験手法

X-RAY DIFFRACTION (2.4 Å)