Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds

Abstract

Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effects like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds. The results of docking studies indicate that some of the ginger phenolic compounds demonstrate higher selective PDE4B inhibition than existing selective PDE4B inhibitors. Additionally, 6-gingerol showed the highest PDE4B inhibitory activity as well as selectivity. The comparison of binding mode of PDE4B/6-gingerol and PDE4D/6-gingerol complexes revealed that 6-gingerol formed additional hydrogen bond and hydrophobic interactions with active site and control region 3 (CR3) residues in PDE4B, which were primarily responsible for its PDE4B selectivity. The results of binding free energy demonstrated that electrostatic energy is the primary factor in elucidating the mechanism of PDE4B inhibition by 6-gingerol. Dynamic cross-correlation studies also supported the results of docking and molecular dynamics simulation. Finally, a small library of molecules were designed based on the identified structural features, majority of designed molecules showed higher PDE4B selectivity than 6-gingerol. These results provide important structural features for designing new selective PDE4B inhibitors as anti-inflammatory drugs and promising candidates for synthesis and pre-clinical pharmacological investigations.

Comparative Studies of Palmatine with Metformin and Glimepiride on the Modulation of Insulin Dependent Signaling Pathway In Vitro, In Vivo & Ex Vivo

“…The RMSD values for the co-crystallized ligand pose vs. docked pose are documented in Table 1, while the overlaid poses are shown in Figure 4. The RMSD value lower than 2.0 Å was considered a validation of the docking procedure [15,16]. Acceptable RMSD values were obtained for the docking protocol adopted, indicating the ability of the docking protocol to reproduce the original co-crystalized pose [17,18].…”

Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor

“…This region includes the hydrophobic residues that are less conserved than M pocket. A number of studies have shown that the PDE4 inhibitors share two features, a planar ring structure held within the hydrophobic residues of the P-clamp (PHE446 in PDE4B vs PHE538 in PDE4D at the roof of the P-clamp and ILE410 and PHE414 in PDE4B vs ILE502 and PHE506 in PDE4D on the floor of the binding site) ( Tripuraneni and Azam, 2016 ) and a hydrogen bonding interaction with the invariant glutamine residue (GLN443 in PDE4B vs GLN535 in PDE4D) ( Card et al., 2004 ; Xing et al., 2017 ). The cAMP is recognized by enzyme upon the formation of a hydrogen bond with the Q pocket.…”

“…Each complex was prepared by using Antechamber, Parmchk and AMBER force field (ff14SB). The Antechamber and Parmchk were used to assign general AMBER force field (GAFF) parameters, calculate the restricted electrostatic potential (RESP) under Gaussian g09 and generate the prepi and frcmod files for the ligands ( Xing et al., 2017 ). While; the ff14SB was used to describe the molecular characteristics of the complex and obtain the topology (top) and coordinate (crd) files for each complex ( Pérez et al., 2007 ).…”

Nutraceutical Screening in a Zebrafish Model of Muscular Dystrophy: Gingerol as a Possible Food Aid

“…The reason for the efficacy of gingerol in the zebrafish model of DMD is unclear but could be related to its known biological (including anti-inflammatory and anti-oxidant) activities [36]. Moreover, gingerol is also a selective inhibitor of subtype B of the phosphodiesterase-4 family of enzymes, which are involved in regulating the release of anti-inflammatory and pro-inflammatory cytokines within cells [37]. Previous drug-screening studies conducted in sapje zebrafish showed that sildenafil, an inhibitor of phosphodiesterase-5, whose mechanism of action is believed to affect the Hmox1 pathway and increase Hmox1 protein expression, could improve locomotion and survival [16] in sapje larvae.…”