7CBQ

Crystal structure of PDE4D catalytic domain in complex with Apremilast

7CBQ の概要

• エントリーDOI: 10.2210/pdb7cbq/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, MAGNESIUM ION, ZINC ION, ... (6 entities in total)
• 機能のキーワード: pde4d, inhibitor, complex structure, metal binding protein, 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: 82000.19

構造登録者

Zhang, X.L.,Xu, Y.C. (登録日: 2020-06-13, 公開日: 2021-01-27, 最終更新日: 2023-11-29)

主引用文献

Zhang, R.,Li, H.,Zhang, X.,Li, J.,Su, H.,Lu, Q.,Dong, G.,Dou, H.,Fan, C.,Gu, Z.,Mu, Q.,Tang, W.,Xu, Y.,Liu, H.
Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.
Eur.J.Med.Chem., 211:113004-113004, 2021

PubMed Abstract: Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.

PubMed: 33218684
DOI: 10.1016/j.ejmech.2020.113004

実験手法

X-RAY DIFFRACTION (1.59 Å)