PHARMACOPHORE SCREENING AND MOLECULAR DOCKING OF PHYTOCONSTITUENTS IN POLYGONUM SAGITTATUM FOR CYCLOOXYGENASE-2 INHIBITORS DISCOVERY.


Sandra Megantara, Agung Yodha Mw, Sahidin I, Ajeng Diantini, Jutti Levita

Abstract


 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; AUC100% 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.


Keywords


Arrowleaf tearthumb, Celecoxib, Mefenamic acid, Nonsteroidal anti-inflammatory drugs, PGH2, Polygonaceae, Prostaglandin.

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About this article

Title

PHARMACOPHORE SCREENING AND MOLECULAR DOCKING OF PHYTOCONSTITUENTS IN POLYGONUM SAGITTATUM FOR CYCLOOXYGENASE-2 INHIBITORS DISCOVERY.

Topics

Molecular pharmacology; in silico pharmacology; computational medicinal chemistry

Keywords

Arrowleaf tearthumb, Celecoxib, Mefenamic acid, Nonsteroidal anti-inflammatory drugs, PGH2, Polygonaceae, Prostaglandin.

DOI

10.22159/ajpcr.2018.v11i1.21154

Date

01-01-2018

Additional Links

Manuscript Submission

Journal

Asian Journal of Pharmaceutical and Clinical Research
Vol 11 Issue 1 January 2018 Page: 83-88

Print ISSN

0974-2441

Online ISSN

2455-3891

Statistics

72 Views | 115 Downloads

Authors & Affiliations

Sandra Megantara
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia.
Indonesia

Agung Yodha Mw
Department of Pharmacy, Faculty of Pharmacy, Universitas Halu Oleo, Kendari 93232, Indonesia.
Indonesia

Sahidin I
Department of Pharmacy, Faculty of Pharmacy, Universitas Halu Oleo, Kendari 93232, Indonesia.
Indonesia

Ajeng Diantini
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363.
Indonesia

Jutti Levita
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363.
Indonesia


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