3QPP

Structure of PDE10-inhibitor complex

3QPP の概要

• エントリーDOI: 10.2210/pdb3qpp/pdb
• 関連するPDBエントリー: 2O8H 2OVV 2OVY 3QPN 3QPO
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: phosphodiesterase inhibitors, structure-based drug design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats)
• 細胞内の位置: Cytoplasm: Q9QYJ6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42494.35

構造登録者

Pandit, J.,Marr, E.S. (登録日: 2011-02-14, 公開日: 2011-06-15, 最終更新日: 2024-02-21)

主引用文献

Helal, C.J.,Kang, Z.,Hou, X.,Pandit, J.,Chappie, T.A.,Humphrey, J.M.,Marr, E.S.,Fennell, K.F.,Chenard, L.K.,Fox, C.,Schmidt, C.J.,Williams, R.D.,Chapin, D.S.,Siuciak, J.,Lebel, L.,Menniti, F.,Cianfrogna, J.,Fonseca, K.R.,Nelson, F.R.,O'Connor, R.,Macdougall, M.,McDowell, L.,Liras, S.
Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia.
J.Med.Chem., 54:4536-4547, 2011

PubMed Abstract: Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

PubMed: 21650160
DOI: 10.1021/jm2001508

実験手法

X-RAY DIFFRACTION (1.8 Å)