The Next Generation of Phosphodiesterase Inhibitors:  Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases

Manallack, David T.; Hughes, Richard A.; Thompson, Phillip E.

doi:10.1021/jm040217u

Cited by 118 publications

(70 citation statements)

References 67 publications

(165 reference statements)

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“…21) This process is generally under negative feedback regulation by phosphodiesterases (PDEs) that degrade cAMP to AMP. 22) Ramage et al have shown that the hyphal regulatory gene EFG1 is required for normal biofilm growth. 15,16) Surface adhesin ALS3 and hyphae specific gene HWP1 have a pivotal role in biofilm formation.…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Effect of a Macrocyclic Bisbibenzyl Riccardin D on the Biofilms of <i>Candida albicans</i>

Cheng

Sun

et al. 2009

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 99%

The Inhibitory Effect of a Macrocyclic Bisbibenzyl Riccardin D on the Biofilms of <i>Candida albicans</i>

Cheng

Sun

et al. 2009

Biological & Pharmaceutical Bulletin

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“…The docking study of new selective PDE4 inhibitors was facilitated by the published crystal structures of PDE4. 32,58,59) The docking results showed good correlation between the enzymatic activity of our compounds and their binding interactions as well as their Gold Fitness scores.…”

Section: )mentioning

confidence: 74%

Design, Synthesis and Biological Evaluation of Novel Quinazoline-Based Anti-inflammatory Agents Acting as PDE4B Inhibitors

Serya

Abbas

Ismail

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of quinzoline based compounds (IIIa-d, VIa-f, IXa-f) were designed, synthesized and screened for their inhibitory activity towards the PDE4B isoform. The in vivo anti-inflammatory effect of the titled compounds (IIIa-d, VIa-f, IXa-f) as well as their effect on the level of tumor necrosis factor (TNF-α) were evaluated. Among all of the synthesized compounds, IXb, IXd and IXf, exhibited good inhibitory activity against PDE4B enzyme with inhibition percentages of 42, 62 and 68%, respectively. Most of the tested compounds showed potent anti-inflammatory activity compared to indomethacin with a marked decrease in TNF-α level. The ulcerogenic effect of the tested compounds was also examined. The gastric mucosa of the tested animals remained intact after oral administration of the hit compounds. Additionally, docking study was used to explore the possible binding mode of the active compounds on the PDE4B enzyme as well as to illustrate the selectivity of the active hits on the PDE4B isoform.

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“…6 All the ligands cocrystallized with different PDE isoforms also had a hydrogen bonding interaction with a conserved glutamine residue. 5 Molecular docking using FlexX produced docked poses far away from the active site when compared with the GOLDpredicted poses. As a representative example, a comparison of FlexX-predicted (magenta carbon) and GOLD-predicted (orange carbon) binding conformation of 23, one of the most active spiroquinazolinones, is shown in Figure 2.…”

Section: Docking Resultsmentioning

confidence: 99%

“…1,4 Among the 11 different PDE isoforms, PDE4, 7, and 8 are selective for cAMP; PDE5, 6, and 9 hydrolyze cGMP specifically; and PDE1, 2, 3, 10, and 11 can hydrolyze both cyclic nucleotides. 5 Selectivity for the substrate is determined by the ''glutamine switch mechanism.'' 6 A conserved glutamine residue present in the active site determines the selectivity for incoming nucleotides.…”

Section: Introductionmentioning

confidence: 99%

Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

Daga

Doerksen

2008

J Comput Chem

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A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and pi-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC(50) < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC(50) > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition.

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The Next Generation of Phosphodiesterase Inhibitors: Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases

Cited by 118 publications

References 67 publications

The Inhibitory Effect of a Macrocyclic Bisbibenzyl Riccardin D on the Biofilms of <i>Candida albicans</i>

The Inhibitory Effect of a Macrocyclic Bisbibenzyl Riccardin D on the Biofilms of <i>Candida albicans</i>

Design, Synthesis and Biological Evaluation of Novel Quinazoline-Based Anti-inflammatory Agents Acting as PDE4B Inhibitors

Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

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