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Machine learning models to predict ligand binding affinity for the orexin 1 receptor

Authors :
Vanessa Y. Zhang
Shayna L. O’Connor
William J. Welsh
Morgan H. James
Source :
Artificial Intelligence Chemistry, Vol 2, Iss 1, Pp 100040- (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of several behavioral disorders, including drug seeking and overeating. However, currently there are no selective OX1R antagonists approved for clinical use, fueling demand for novel compounds that act at this target. In this study, we meticulously curated a dataset comprising over 1300 OX1R ligands using a stringent filter and criteria cascade. Subsequently, we developed highly predictive quantitative structure-activity relationship (QSAR) models employing the optimized hyper-parameters for the random forest machine learning algorithm and twelve 2D molecular descriptors selected by recursive feature elimination with a 5-fold cross-validation process. The predictive capacity of the QSAR model was further assessed using an external test set and enrichment study, confirming its high predictivity. The practical applicability of our final QSAR model was demonstrated through virtual screening of the DrugBank database. This revealed two FDA-approved drugs (isavuconazole and cabozantinib) as potential OX1R ligands, confirmed by radiolabeled OX1R binding assays. To our best knowledge, this study represents the first report of highly predictive QSAR models on a large comprehensive dataset of diverse OX1R ligands, which should prove useful for the discovery and design of new compounds targeting this receptor.

Details

Language :
English
ISSN :
29497477
Volume :
2
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Artificial Intelligence Chemistry
Publication Type :
Academic Journal
Accession number :
edsdoj.4e59885beaf4219963705c995b0d978
Document Type :
article
Full Text :
https://doi.org/10.1016/j.aichem.2023.100040