Scaffold Fusion and SAR Transfer with a Chemical Language Model Generates Novel Liver X Receptor Modulators
Open Access
- 23 October 2025
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 68 (21) , 22588-22598
Abstract
Liver X receptors (LXRs) are promising targets for metabolic disorders including atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we employed a chemical language model (CLM) for LXR modulator design in an explorative fashion and observed that structural features from different LXR modulator templates were merged, and structure–activity relationship (SAR) knowledge was transferred. The generated computational designs demonstrated LXR modulation with diverse activity profiles and selective modulator properties, including a promising lipolytic activity of an inverse LXR agonist in an in vitro MASLD model that warrants its further development to improve ADME properties.Keywords
Funding Information
- Stiftung Polytechnische Gesellschaft Frankfurt am Main
- Hans und Ria Messer Stiftung (Z_HMS_11/022)
This publication has 49 references indexed in Scilit:
- Chemical language models for molecular designMolecular Informatics, 2023
- De Novo Design of Nurr1 Agonists via Fragment-Augmented Generative Deep Learning in Low-Data RegimeJournal of Medicinal Chemistry, 2023
- Beam Search for Automated Design and Scoring of Novel ROR Ligands with Machine Intelligence**Angewandte Chemie International Edition, 2021
- De Novo Design of Bioactive Small Molecules by Artificial IntelligenceMolecular Informatics, 2018
- Functional induction of P-glycoprotein efflux pump by phenyl benzenesulfonamides: Synthesis and biological evaluation of T0901317 analogsEuropean Journal of Medicinal Chemistry, 2016
- Synthesis and inhibitory activity on hepatitis C virus RNA replication of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analogsBioorganic & Medicinal Chemistry Letters, 2014
- X-Ray Structures of the LXRα LBD in Its Homodimeric Form and Implications for Heterodimer SignalingJournal of Molecular Biology, 2010
- T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXRFEBS Letters, 2007
- T0901317 is a dual LXR/FXR agonistMolecular Genetics and Metabolism, 2004
- NER, a new member of the gene family encoding the human steroid hormone nuclear receptorGene, 1994