期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 35, 页码 19477-19482出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202104405
关键词
de novo design; deep learning; drug discovery; neural network; nuclear receptor
资金
- Swiss National Science Foundation [205321_182176]
- RETHINK initiative at ETH Zurich
- Novartis Forschungsstiftung (FreeNovation grant AI in Drug Discovery)
- Projekt DEAL
- Swiss National Science Foundation (SNF) [205321_182176] Funding Source: Swiss National Science Foundation (SNF)
Chemical language models coupled with the beam search algorithm were used to automate molecule design and scoring, resulting in the discovery of novel inverse agonists for retinoic acid receptor-related orphan receptors (RORs). These designs were synthesizable in three reaction steps and exhibited low-micromolar to nanomolar potency towards RORg, showcasing the potential of generative artificial intelligence in data-driven drug discovery.
Chemical language models enable de novo drug design without the requirement for explicit molecular construction rules. While such models have been applied to generate novel compounds with desired bioactivity, the actual prioritization and selection of the most promising computational designs remains challenging. Herein, we leveraged the probabilities learnt by chemical language models with the beam search algorithm as a model-intrinsic technique for automated molecule design and scoring. Prospective application of this method yielded novel inverse agonists of retinoic acid receptor-related orphan receptors (RORs). Each design was synthesizable in three reaction steps and presented low-micromolar to nanomolar potency towards RORg. This model-intrinsic sampling technique eliminates the strict need for external compound scoring functions, thereby further extending the applicability of generative artificial intelligence to data-driven drug discovery.
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