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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

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



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