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Structure-based identification of dual ligands at the A2AR and PDE10A with anti-proliferative effects in lung cancer cell-lines.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Winfield, Ian 
Carvalho, Sabrina 

Abstract

Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val84 displacement as a novel conformational descriptor of A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.

Description

Keywords

A2AR, Anti‐proliferative, Docking, Dual target, Lung cancer, MD simulations, NSCLC, PDE10A, Structure‐based design, Triazoloquinazolines, Virtual screening

Journal Title

J Cheminform

Conference Name

Journal ISSN

1758-2946
1758-2946

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (336159)