Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma

Bassam M. Ayoub, Yasmeen M. Attia, Mahmoud S. Ahmed

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted.

Original languageEnglish (US)
Pages (from-to)858-866
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Purinergic P1 Receptors
Computer Simulation
Hepatocellular Carcinoma
Dipeptidyl-Peptidase IV Inhibitors
G2 Phase
Caspase 3
Cell Division
Down-Regulation
Apoptosis
Gene Expression
Cell Line
Linagliptin
Pharmaceutical Preparations
Proteins

Keywords

  • adenosine 3 receptor
  • Drug repositioning
  • hepatocellular carcinoma
  • linagliptin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

@article{eb96d8588f314e80bc4cfc60458af5e4,
title = "Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma",
abstract = "Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted.",
keywords = "adenosine 3 receptor, Drug repositioning, hepatocellular carcinoma, linagliptin",
author = "Ayoub, {Bassam M.} and Attia, {Yasmeen M.} and Ahmed, {Mahmoud S.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1080/14756366.2018.1462801",
language = "English (US)",
volume = "33",
pages = "858--866",
journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",
issn = "1475-6366",
publisher = "Informa Healthcare",
number = "1",

}

TY - JOUR

T1 - Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma

AU - Ayoub, Bassam M.

AU - Attia, Yasmeen M.

AU - Ahmed, Mahmoud S.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted.

AB - Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted.

KW - adenosine 3 receptor

KW - Drug repositioning

KW - hepatocellular carcinoma

KW - linagliptin

UR - http://www.scopus.com/inward/record.url?scp=85047255020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047255020&partnerID=8YFLogxK

U2 - 10.1080/14756366.2018.1462801

DO - 10.1080/14756366.2018.1462801

M3 - Article

C2 - 29768061

AN - SCOPUS:85047255020

VL - 33

SP - 858

EP - 866

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

SN - 1475-6366

IS - 1

ER -