2VCX

Complex structure of prostaglandin D2 synthase at 2.1A.

2VCX の概要

• エントリーDOI: 10.2210/pdb2vcx/pdb
• 関連するPDBエントリー: 1IYH 1IYI 1V40 2VCQ 2VCW 2VCZ 2VD0
• 分子名称: GLUTATHIONE-REQUIRING PROSTAGLANDIN D SYNTHASE, MAGNESIUM ION, GLUTATHIONE, ... (5 entities in total)
• 機能のキーワード: prostaglandin biosynthesis, fatty acid biosynthesis, prostaglandin d2 synthase, pgds, asthma, cytoplasm, isomerase, lipid synthesis
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: O60760
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 95443.08

構造登録者

Hohwy, M.,Spadola, L.,Lundquist, B.,von Wachenfeldt, K.,Persdotter, S.,Hawtin, P.,Dahmen, J.,Groth-Clausen, I.,Folmer, R.H.A.,Edman, K. (登録日: 2007-09-27, 公開日: 2008-04-15, 最終更新日: 2023-12-13)

主引用文献

Hohwy, M.,Spadola, L.,Lundquist, B.,Hawtin, P.,Dahmen, J.,Groth-Clausen, I.,Nilsson, E.,Persdotter, S.,Von Wachenfeldt, K.,Folmer, R.H.A.,Edman, K.
Novel Prostaglandin D Synthase Inhibitors Generated by Fragment-Based Drug Design.
J.Med.Chem., 51:2178-, 2008

PubMed Abstract: We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein-ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC 50 below 1 microM in the in vitro assay. The best inhibitor (IC 50 = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway.

PubMed: 18341273
DOI: 10.1021/JM701509K

実験手法

X-RAY DIFFRACTION (2.1 Å)