2. Academic Validation
  3. Scaffold Fusion and SAR Transfer with a Chemical Language Model Generates Novel Liver X Receptor Modulators

Scaffold Fusion and SAR Transfer with a Chemical Language Model Generates Novel Liver X Receptor Modulators

  • J Med Chem. 2025 Nov 13;68(21):22588-22598. doi: 10.1021/acs.jmedchem.5c01551.
Nils Christiaan Bandomir 1,  Tim Hörmann 2,  Annette Kärcher 1,  Astrid Kaiser 1,  Daniel Merk 2,  Pascal Heitel 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
  • 2 Department of Pharmacy, Ludwig-Maximilians-Universität (LMU) München, Butenandtstrasse 5-13, 81377 Munich, Germany.
PMID: 41129410 DOI: 10.1021/acs.jmedchem.5c01551
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.

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