The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay

• Published in: Biochimica et biophysica acta Vol. 1834; no. 10; pp. 2089 - 2096
• Main Authors: Zhao, Peng, Chen, Shang-Ke, Cai, Ying-Hong, Lu, Xiao, Li, Zhe, Cheng, Yuen-Kit, Zhang, Cuixian, Hu, Xiaopeng, He, Xixin, Luo, Hai-Bin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2013
• Subjects: active sites; Binding Sites; Bioassay; bioassays; Biological Assay; Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry; Cyclic Nucleotide Phosphodiesterases, Type 4; energy; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; hydrophobicity; Inhibition; inhibitory concentration 50; Kinetics; Mechanism; Modeling; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; molecular models; Phosphodiesterase 4 Inhibitors - chemistry; Phosphodiesterase-4; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Protein Binding; Protein Structure, Tertiary; pterostilbene; resveratrol; Resveratrol analog; Stilbenes - chemistry; Stilbenes - isolation & purification; Structure-Activity Relationship; Thermodynamics; Phosphodiesterase-4; Bioassay; Inhibition; Resveratrol analog; Modeling; Mechanism
• ISSN: 1570-9639; 0006-3002; 1878-1454
• DOI: 10.1016/j.bbapap.2013.07.004

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2′,3,5′,5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R2=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products. [Display omitted] •Pterostilbene represents a different binding pattern from other two compounds.•Hydrophobic/aromatic forces play the major contributions to the binding of ligands.•A linear correlation was derived between the predicted ΔGbind and experimental ΔGbind′.