Pharmacophore Modeling and Virtual Screening for the Discovery of New type 4 cAMP Phosphodiesterase (PDE4) Inhibitors

Niu, Miaomiao; Dong, Feng-gong; Tang, Shi; Fida, Guissi; Qin, Jingyi; Qiu, Jiadan; Liu, Kangbo; Gao, Weidong; Gu, Yueqing

doi:10.1371/journal.pone.0082360

Cited by 31 publications

(17 citation statements)

References 18 publications

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“…The aromatic ring of the all known PDE inhibitors has shown crucial face to face -stacking interactions with Phe446. A study by Niu et al (Niu et al, 2013) also reported that two hydrogen bond acceptors, one hydrophobic ring and an aromatic group are critical Pharmacophoric features for PDE inhibitors (Niu et al, 2013). The compounds shown in Fig.…”

Section: Pharmacophoric Features In For Phosphodiesterases Inhibitorsmentioning

confidence: 96%

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer’s disease

Kumar

Sharma

Singh

et al. 2015

Mechanisms of Ageing and Development

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Section: Pharmacophoric Features In For Phosphodiesterases Inhibitorsmentioning

confidence: 96%

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer’s disease

Kumar

Sharma

Singh

et al. 2015

Mechanisms of Ageing and Development

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“…The GH score ranges from 0 (indicates the null model) to 1 (indicates the ideal model). When the GH score exceeds 0.7, the model is very good to identify the active compounds [18,19]. The result was used to screen the pharmacophores of the phytoconstituents isolated from P. sagittatum (Fig.…”

Section: Protein Preparation and Validation Of The Pharmacophore Featmentioning

confidence: 99%

Pharmacophore Screening and Molecular Docking of Phytoconstituents in Polygonum Sagittatum for Cyclooxygenase-2 Inhibitors Discovery.

Megantara¹,

Mw²,

Sahidin³

et al. 2018

Asian J Pharm Clin Res

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Objective: The objective of this study is to discover cyclooxygenase (COX-2) inhibitors from Polygonum sagittatum (Polygonaceae), by screening the pharmacophores based on the interaction of mefenamic acid with COX-2, followed by molecular docking with COX-2. Methods:The protein crystal structure of human COX-2 in complex with mefenamic acid (PDB code: 5IKR) was selected, its ligand-protein interaction was studied by employing LigandScout to obtain the pharmacophore features. The features were validated against PGH2 database provided at http://dude.docking.org/targets/pgh2, and the result was used to screen the pharmacophores of the phytoconstituents isolated from P. sagittatum. Furthermore, a molecular docking of the phytoconstituents into COX-2 binding pocket was performed. The compounds were generated using MarvinSketch, and the energy was optimized by employing LigandScout MMFF94. Celecoxib and mefenamic acid, selective COX-2 inhibitors, were used as the standard drugs. Results:The pharmacophore features obtained were aromatic ring (hydrophobicity) and two hydrogen bond acceptors, which are proved valid against PGH2 training set (GH score = 0.78; AUC 100% receiver operating characteristic curve = 0.97). There are four phytoconstituents (quercetin, protocatechuic acid, vanicoside A, and vanicoside B) that fit the features, and therefore, are predicted to be active in inhibiting COX-2. The docking reveals that three phytoconstituents (methyl-4-hydroxycinnamate, quercetin, and methyl gallate) interact with Tyr385, an important amino acid residue in COX-2 binding pocket. Quercetin is the best in inhibiting the enzyme (docking score −8.60 kcal/mol; inhibition constant 0.5 µM), compared to mefenamic acid (docking score −8.90 kcal/mol; inhibition constant 0.3 µM) and celecoxib (docking score −10.00 kcal/mol; inhibition constant 0.05 µM).Conclusions: Phytoconstituents in P. sagittatum fit the pharmacophore features generated from mefenamic acid and COX-2 complex; therefore, they might be potential in inhibiting COX-2 enzyme. Their binding modes are more similar to that of mefenamic acid than of celecoxib. Of those, quercetin is the best in inhibiting the enzyme. Its inhibitory activity is equal to mefenamic acid but is weaker than celecoxib.

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“…Pharmaceutical research in the field of chronic inflammatory disorders has made a step forward by developing new PDE4 inhibitors with a higher therapeutic index [88]. Apremilast, introduced to the clinic [35,89] and approved in the USA for the treatment of PsA [90], is one of these novel drugs, thus representing a promising tool for the medical treatment of other diseases mediated by the immune system.…”

Section: Apremilast In Immune-mediated Inflammatory Disordersmentioning

confidence: 99%

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

Spadaccini

D’Alessio

Peyrin–Biroulet

et al. 2017

IJMS

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Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. Aim. To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. Methods. Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. Results. PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. Conclusion. In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD.

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Pharmacophore Modeling and Virtual Screening for the Discovery of New type 4 cAMP Phosphodiesterase (PDE4) Inhibitors

Cited by 31 publications

References 18 publications

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer’s disease

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer’s disease

Pharmacophore Screening and Molecular Docking of Phytoconstituents in Polygonum Sagittatum for Cyclooxygenase-2 Inhibitors Discovery.

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

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