Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase

Khozirah Shaari, Velan Suppaiah, Kok Wai Lam, Johnson Stanslas, Bimo Ario Tejo, Daud Ahmad Israf, Faridah Abas, Intan Safinar Ismail, Nor Hasifi Shuaib, Seema Zareen, Nordin Hj Lajis

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC 50 value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC4 with an IC 50 value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC 50 value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of 13.45 (electrostatic) and 5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56 Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.

Original languageEnglish
Pages (from-to)6340-6347
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number21
DOIs
Publication statusPublished - 1 Nov 2011

Fingerprint

Rutaceae
Arachidonate 5-Lipoxygenase
Bioassay
Static Electricity
Biological Assay
Electrostatics
Catalytic Domain
Anti-Inflammatory Agents
Metals
Phloroglucinol
Leukotriene C4
Prostaglandin-Endoperoxide Synthases
Chelation
Bioactivity
Soybeans
Human Activities
Hydroxyl Radical
Computer Simulation
Oxidation-Reduction
Metal ions

Keywords

  • Acylpholoroglucinol
  • Anti-inflammatory
  • Cyclooxygenase
  • Dual LOX/COX inhibitors
  • Lipoxygenase
  • Melicope ptelefolia
  • Rutacecae

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase. / Shaari, Khozirah; Suppaiah, Velan; Lam, Kok Wai; Stanslas, Johnson; Tejo, Bimo Ario; Israf, Daud Ahmad; Abas, Faridah; Ismail, Intan Safinar; Shuaib, Nor Hasifi; Zareen, Seema; Lajis, Nordin Hj.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 21, 01.11.2011, p. 6340-6347.

Research output: Contribution to journalArticle

Shaari, Khozirah ; Suppaiah, Velan ; Lam, Kok Wai ; Stanslas, Johnson ; Tejo, Bimo Ario ; Israf, Daud Ahmad ; Abas, Faridah ; Ismail, Intan Safinar ; Shuaib, Nor Hasifi ; Zareen, Seema ; Lajis, Nordin Hj. / Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 21. pp. 6340-6347.
@article{982131f00922484d8871907266cea5a5,
title = "Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase",
abstract = "A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC 50 value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC4 with an IC 50 value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC 50 value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of 13.45 (electrostatic) and 5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56 {\AA} hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.",
keywords = "Acylpholoroglucinol, Anti-inflammatory, Cyclooxygenase, Dual LOX/COX inhibitors, Lipoxygenase, Melicope ptelefolia, Rutacecae",
author = "Khozirah Shaari and Velan Suppaiah and Lam, {Kok Wai} and Johnson Stanslas and Tejo, {Bimo Ario} and Israf, {Daud Ahmad} and Faridah Abas and Ismail, {Intan Safinar} and Shuaib, {Nor Hasifi} and Seema Zareen and Lajis, {Nordin Hj}",
year = "2011",
month = "11",
day = "1",
doi = "10.1016/j.bmc.2011.09.001",
language = "English",
volume = "19",
pages = "6340--6347",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "21",

}

TY - JOUR

T1 - Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase

AU - Shaari, Khozirah

AU - Suppaiah, Velan

AU - Lam, Kok Wai

AU - Stanslas, Johnson

AU - Tejo, Bimo Ario

AU - Israf, Daud Ahmad

AU - Abas, Faridah

AU - Ismail, Intan Safinar

AU - Shuaib, Nor Hasifi

AU - Zareen, Seema

AU - Lajis, Nordin Hj

PY - 2011/11/1

Y1 - 2011/11/1

N2 - A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC 50 value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC4 with an IC 50 value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC 50 value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of 13.45 (electrostatic) and 5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56 Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.

AB - A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC 50 value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC4 with an IC 50 value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC 50 value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of 13.45 (electrostatic) and 5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56 Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.

KW - Acylpholoroglucinol

KW - Anti-inflammatory

KW - Cyclooxygenase

KW - Dual LOX/COX inhibitors

KW - Lipoxygenase

KW - Melicope ptelefolia

KW - Rutacecae

UR - http://www.scopus.com/inward/record.url?scp=80054961622&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054961622&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.09.001

DO - 10.1016/j.bmc.2011.09.001

M3 - Article

VL - 19

SP - 6340

EP - 6347

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 21

ER -