Insight into Inhibitory Mechanism of PDE4D by Dietary Polyphenols Using Molecular Dynamics Simulations and Free Energy Calculations

Abstract

Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer’s disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer’s disease with a potentially wider therapeutic window and fewer adverse side effects.

Mechanistic Insights into Biological Activities of Polyphenolic Compounds from Rosemary Obtained by Inverse Molecular Docking

“…The inverse molecular docking protocol based on the CANDOCK algorithm resulted in score variations for the detection of true target proteins (TG determined from PC has a value of 0.171), which in combination with ROC AUC above 0.6 indicates that the protocol provides good results in agreement with the experiments [ 61 ]. Moreover, our inverse molecular docking protocol has been already extensively validated by Fine and Konc et al [ 55 ], Furlan et al [ 50 , 130 ], Kores et al [ 49 , 131 ], and Jukič et al [ 132 ] using different molecules of interest.…”

“…Natural plant-based compounds play an important role in the development of novel drugs as they may possess several advantages over conventional synthetic compounds, namely, fewer side effects, lower long-term toxicity, and versatile biological effects [ 130 ]. We report the potential targets of the major compounds from Rosmarinus officinalis , including the diterpenes carnosic acid, carnosol, and rosmanol, as well as the polyphenolic ester rosmarinic acid.…”

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

“…A study on inhibition of Fts-Z with compounds Coupene, Proximadiol, and Menthone had a docking score of −6.2 Kcalmol −1 , −6 Kcalmol −1 and −5.7 Kcalmol −1 , which are lower than docking score of ADMA dealt in our finding [ 8 ]. Another study on verticiol as a Fts- Z inhibitor exhibits the docking score of −4.72 Kcalmol −1 [ 58 ]. These compounds had binding affinity near to ADMA reported in our study.…”

“…Another group of scientists exploring the 180 endophytic fungal strains from Chinese medicinal plant Panax notoginseng found compound Brasiliamide J-a and Brasiliamide J-b from species Penicillium janthinellum to be a potential inhibitor of Fts-Z against B. subtilis (PDB ID-2VXY), with a binding affinity of −111 Kcalmol −1 forming H − bonds with residues Glu 139 and Gly 107 and hydrophobic bonds Asn 166, Gly 104, Gly 21, and Asn 25 for compound Brasiliamide J-a and −122 Kcalmol −1 forming H − bonds with Asn 25 and hydrophobic bonds with Met 105, Glu 139, and Phe 183 for compound Brasiliamide J-b and against S.aureus (PDB ID-3VOB) [ 61 ]. Further, an In-silico study revealed that quinazoline derivatives, Zantrin Z3 and ZZ3, bind Mycobacterium tuberculosis Fts-Z protein (PDB ID- 1RQ7-chain A) near the H6/H7 loop and do not affect hydrolysis of GTP, but they are efficient against the aggregation of Fts-Z [ 58 ]. Ballu and co-workers performed In-silico receptor-based docking experiments and 3D QSAR using CoMFA and CoMSIA methods to understand binding interactions of 42 molecules (oxazole-benzamide derivatives and aryl alkoxy benzamide derivatives) with the receptor (PDB ID- 3VOB) and highlighted the role of residues Val 207, Leu 209, and Asn 263 in the binding of inhibitors to Fts-Z protein [ 62 ].…”

Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations

“…E2 and OHT were redocked in the binding sites of ERα1 and ERα2, respectively, to validate the docking procedure and parameters [56]. The complexes from redocking were superimposed with the X-ray crystal structures 1GWR and 3ERT, respectively, to calculate RMSD values for the ligands (Figure 8).…”