Phosphodiesterase-4, the primary enzyme responsible for cAMP degradation in the majority of immune and inflammatory cells, plays a critical role in the regulation of intracellular cAMP levels. Consequently, small molecular entities capable of inhibiting PDE4 have been employed in the treatment of inflammation-associated disorders, such as chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis (AD), inflammatory bowel diseases (IBD), rheumatic arthritis (RA). In the present investigation, a multi-faceted approach was employed to identify novel PDE4 inhibitors, utilizing the co-crystallization structure of PDE4B available in the Protein Data Bank (PDB) database, drug-like screening, false positive filtration, similarity and ADMET screen, as well as molecular docking via multiple software platforms, in conjunction with bioactivity assays. A thiazol-3-propanamides derivative, designated MR9, was discovered to inhibit PDE4B activity with IC50 values of 2.12 & mu;M and suppress cellular inflammatory factor TNF-& alpha; release with an EC50 value of 3.587 & mu;M. These findings suggest that the innovative active scaffold of MR9 offers a promising foundation for further structural refinement aimed at developing more potent PDE4 inhibitors.
[1]Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochemistry & Plant Resources Wes, Kunming 650201, Peoples R China.
[2]Kunming Med Univ, Sch Pharmaceut Sci, Yunnan Key Lab Pharmacol Nat Prod, Kunming 650500, Peoples R China.
[3]Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
(8.0+极速模式)