This title appears in the Scientific Report :
2023
Please use the identifier:
http://dx.doi.org/10.34734/FZJ-2023-02927 in citations.
Please use the identifier: http://dx.doi.org/10.1039/D3SC02352D in citations.
AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology
AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology
Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for in silico screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist...
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Personal Name(s): | Goßen, Jonas |
---|---|
Ribeiro, Rui Pedro / Bier, Dirk / Neumaier, Bernd / Carloni, Paolo / Giorgetti, Alejandro / Rossetti, Giulia (Corresponding author) | |
Contributing Institute: |
Nuklearchemie; INM-5 Jülich Supercomputing Center; JSC Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5 |
Published in: | Chemical science, 14 (2023) 32, S. 8651-8661 |
Imprint: |
Cambridge
RSC
2023
|
DOI: |
10.34734/FZJ-2023-02927 |
DOI: |
10.1039/D3SC02352D |
Document Type: |
Journal Article |
Research Program: |
Brain Dysfunction and Plasticity Neuroscientific Data Analytics and AI |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1039/D3SC02352D in citations.
Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for in silico screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model. As a test case, we apply this approach to identify novel antagonists of the human adenosine transmembrane receptor type 2A, an attractive target against Parkinson's disease and cancer. The identified antagonists were tested here in a radio ligand binding assay. Among those, we found a promising ligand whose chemotype differs significantly from all so-far reported antagonists, with a binding affinity of 310 ± 23.4 nM. Thus, our protocol emerges as a powerful approach to identify promising ligand candidates with novel chemotypes while preserving antagonistic potential and affinity in the nanomolar range |