6IMI

Crystal structure of PDE4D complexed with a novel inhibitor

6IMI の概要

• エントリーDOI: 10.2210/pdb6imi/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, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 81549.75

構造登録者

Zhang, X.,Su, H.,Xu, Y. (登録日: 2018-10-23, 公開日: 2019-10-23, 最終更新日: 2024-03-27)

主引用文献

Zhang, X.,Dong, G.,Li, H.,Chen, W.,Li, J.,Feng, C.,Gu, Z.,Zhu, F.,Zhang, R.,Li, M.,Tang, W.,Liu, H.,Xu, Y.
Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
J.Med.Chem., 62:5579-5593, 2019

PubMed Abstract: Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.

PubMed: 31099559
DOI: 10.1021/acs.jmedchem.9b00518

実験手法

X-RAY DIFFRACTION (1.46 Å)