Next Article in Journal
Microemulsion and Sol-Gel Synthesized ZrO2-MgO Catalysts for the Liquid-Phase Dehydration of Xylose to Furfural
Next Article in Special Issue
Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents
Previous Article in Journal
Acid-Induced Rearrangement of Epoxygermacranolides: Synthesis of Furanoheliangolides and Cadinanes from Nobilin
Article Menu
Issue 12 (December) cover image

Export Article

Open AccessArticle
Molecules 2017, 22(12), 2254;

GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents

School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand
Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New Zealand
Author to whom correspondence should be addressed.
Received: 30 November 2017 / Revised: 11 December 2017 / Accepted: 15 December 2017 / Published: 18 December 2017
(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)
Full-Text   |   PDF [6559 KB, uploaded 18 December 2017]   |  


A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low µM region, four as an antagonist; CRL-RAMP3 (IC50—11.9 µM), NPSR1B (IC50—1.0 µM), PRLHR (IC50—9.3 µM), and CXCR4 (IC50—6.9 µM). Finally, one agonist, GPRR35, was found (EC50 of 7.5 µM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly-identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development. View Full-Text
Keywords: docking; molecular and homology modelling; drug discovery; chemical space docking; molecular and homology modelling; drug discovery; chemical space

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Zafar, A.; Sari, S.; Leung, E.; Pilkington, L.I.; Van Rensburg, M.; Barker, D.; Reynisson, J. GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents. Molecules 2017, 22, 2254.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top