Combining Experimental Assays and Molecular Modeling to Evaluate Monosubstituted Cinnamic Acid Derivatives as PDE4B...

In this study, we evaluated the inhibitory effects of cinnamic acid and its 18 commercially available derivatives on phosphodiesterase 4 (PDE4) to investigate their therapeutic potential for chronic obstructive pulmonary disease (COPD). Among the tested compounds, p-coumaric acid and trans-4-methoxycinnamic acid exhibited potent PDE4B inhibitory activity (IC₅₀ = 2.2 μM and 8.2 μM, respectively) and notable selectivity over PDE4D, with IC₅₀ values against TNF-α release in human mononuclear cells of 21.5 μM and 30.8 μM, respectively, comparable to rolipram. Structure-activity relationship (SAR) analysis indicated that para-substituted derivatives generally showed higher activity than their meta- or ortho-substituted counterparts. A validated CoMSIA model (q ² = 0.514, r ² = 0.971) highlighted the importance of electrostatic properties, revealing that electron-donating groups at the para position enhance inhibitory activity. Molecular docking illustrated that active derivatives bind in the PDE4B active site, forming key interactions with Gln443 and His234, which was refined by molecular dynamics simulations and free energy calculations. For p-coumaric acid, binding is primarily driven by a strong hydrogen bond with His234, whereas for trans-4-methoxycinnamic acid, enhanced hydrophobic interactions within the M pocket compensate for the lack of this hydrogen bond, revealing a dual mechanism for high-affinity binding. In vivo studies further confirmed significant anti-inflammatory effects, where p-coumaric acid inhibited TNF-α release by 41.1% and LPS-induced neutrophilia by 32.5%. Additionally, in silico ADMET profiling predicted favorable drug-like properties including high oral bioavailability and low CNS penetration, while identifying CYP2C8 inhibition as an optimizable liability. These integrated results underscore monosubstituted cinnamic acids, especially para-hydroxy and para-methoxy derivatives, as privileged scaffolds for developing novel PDE4B-targeted therapeutics for COPD.