6IMR

Crystal structure of PDE4D complexed with a novel inhibitor

Summary for 6IMR

• Entry DOI: 10.2210/pdb6imr/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: pde4d, inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 81998.02

Authors

Zhang, X.L.,Su, H.X.,Xu, Y.C. (deposition date: 2018-10-23, release date: 2019-10-23, Last modification date: 2024-03-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.503 Å)