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Structure-based identification of dual ligands at the A(2A)R and PDE10A with anti-proliferative effects in lung cancer cell-lines
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Title: | Structure-based identification of dual ligands at the A(2A)R and PDE10A with anti-proliferative effects in lung cancer cell-lines |
Authors: | Kalash, L Winfield, I Safitri, D Bermudez, M Carvalho, S Glen, R Ladds, G Bender, A |
Item Type: | Journal Article |
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. |
Issue Date: | 3-Mar-2021 |
Date of Acceptance: | 1-Feb-2021 |
URI: | http://hdl.handle.net/10044/1/93855 |
DOI: | 10.1186/s13321-021-00492-5 |
ISSN: | 1758-2946 |
Publisher: | BioMed Central |
Journal / Book Title: | Journal of Cheminformatics |
Volume: | 13 |
Issue: | 1 |
Copyright Statement: | © The Author(s) 2021 |
Keywords: | Science & Technology Physical Sciences Technology Chemistry, Multidisciplinary Computer Science, Information Systems Computer Science, Interdisciplinary Applications Chemistry Computer Science Docking MD simulations Structure-based design Virtual screening A(2A)R PDE10A Anti-proliferative Dual target Triazoloquinazolines NSCLC Lung cancer A2AR Anti‐proliferative Docking Dual target Lung cancer MD simulations NSCLC PDE10A Structure‐based design Triazoloquinazolines Virtual screening Science & Technology Physical Sciences Technology Chemistry, Multidisciplinary Computer Science, Information Systems Computer Science, Interdisciplinary Applications Chemistry Computer Science Docking MD simulations Structure-based design Virtual screening A(2A)R PDE10A Anti-proliferative Dual target Triazoloquinazolines NSCLC Lung cancer 0303 Macromolecular and Materials Chemistry |
Publication Status: | Published |
Article Number: | ARTN 17 |
Online Publication Date: | 2021-03-03 |
Appears in Collections: | Department of Metabolism, Digestion and Reproduction |
This item is licensed under a Creative Commons License