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

7 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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