6G5J

Secreted phospholipase A2 type X in complex with ligand

6G5J の概要

• エントリーDOI: 10.2210/pdb6g5j/pdb
• 分子名称: Group 10 secretory phospholipase A2, CALCIUM ION, (3~{R})-3-[3-[2-aminocarbonyl-6-(trifluoromethyloxy)indol-1-yl]phenyl]butanoic acid, ... (6 entities in total)
• 機能のキーワード: secretory phospholipase a2 type x spla2x spla2-x phospholipase enzyme inhibitor complex, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37826.02

構造登録者

Sandmark, J.,Oster, L. (登録日: 2018-03-29, 公開日: 2018-09-05, 最終更新日: 2024-10-23)

主引用文献

Giordanetto, F.,Knerr, L.,Nordberg, P.,Pettersen, D.,Selmi, N.,Beisel, H.G.,de la Motte, H.,Mansson, A.,Dahlstrom, M.,Broddefalk, J.,Saarinen, G.,Klingegard, F.,Hurt-Camejo, E.,Rosengren, B.,Wikstrom, J.,Wagberg, M.,Brengdahl, J.,Rohman, M.,Sandmark, J.,Akerud, T.,Roth, R.G.,Jansen, F.,Ahlqvist, M.
Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridine-2-yl}propanoic Acid.
ACS Med Chem Lett, 9:600-605, 2018

PubMed Abstract: A lead generation campaign identified indole-based sPLA-X inhibitors with a promising selectivity profile against other sPLA isoforms. Further optimization of sPLA selectivity and metabolic stability resulted in the design of (-)-, a novel, potent, and selective sPLA-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- was tested in an ApoE murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)- did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

PubMed: 30034586
DOI: 10.1021/acsmedchemlett.7b00507

実験手法

X-RAY DIFFRACTION (1.85 Å)