6RX6

Trypanosoma brucei PTR1 (TbPTR1) in complex with inhibitor 4 (NMT-C0026)

6RX6 の概要

• エントリーDOI: 10.2210/pdb6rx6/pdb
• 関連するPDBエントリー: 6RX0 6RX5
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, methyl 1-[4-[[2,4-bis(azanyl)pteridin-6-yl]methyl-(3-oxidanylpropyl)amino]phenyl]carbonylpiperidine-4-carboxylate, ... (5 entities in total)
• 機能のキーワード: trypanosoma brucei, pteridine reductase, ptr1, tbptr1, pteridine based inhibitors, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 127690.01

構造登録者

Landi, G.,Pozzi, C.,Mangani, S. (登録日: 2019-06-07, 公開日: 2020-07-15, 最終更新日: 2024-01-24)

主引用文献

Pohner, I.,Quotadamo, A.,Panecka-Hofman, J.,Luciani, R.,Santucci, M.,Linciano, P.,Landi, G.,Di Pisa, F.,Dello Iacono, L.,Pozzi, C.,Mangani, S.,Gul, S.,Witt, G.,Ellinger, B.,Kuzikov, M.,Santarem, N.,Cordeiro-da-Silva, A.,Costi, M.P.,Venturelli, A.,Wade, R.C.
Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.
J.Med.Chem., 65:9011-9033, 2022

PubMed Abstract: The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of pteridine reductase 1 (PTR1), nanomolar inhibition of PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC values against while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.

PubMed: 35675511
DOI: 10.1021/acs.jmedchem.2c00232

実験手法

X-RAY DIFFRACTION (1.11 Å)