De Novo Design of Nurr1 Agonists via Fragment-Augmented Generative Deep Learning in Low-Data Regime.

Generative neural networks trained on SMILES can design innovative bioactive molecules de novo . These so-called chemical language models (CLMs) have typically been trained on tens of template molecules for fine-tuning. However, it is challenging to apply CLM to orphan targets with few known ligands. We have fine-tuned a CLM with a single potent Nurr1 agonist as template in a fragment-augmented fashion and obtained novel Nurr1 agonists using sampling frequency for design prioritization. Nanomolar potency and binding affinity of the top-ranking design and its structural novelty compared to available Nurr1 ligands highlight its value as an early chemical tool and as a lead for Nurr1 agonist development, as well as the applicability of CLM in very low-data scenarios.