7CBQ

Crystal structure of PDE4D catalytic domain in complex with Apremilast

Summary for 7CBQ

• Entry DOI: 10.2210/pdb7cbq/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, MAGNESIUM ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: pde4d, inhibitor, complex structure, metal binding protein, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 82000.19

Authors

Zhang, X.L.,Xu, Y.C. (deposition date: 2020-06-13, release date: 2021-01-27, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.59 Å)