De Novo Design of Bioactive Small Molecules by Artificial Intelligence

By D. Merk, Lukas Friedrich, Francesca Grisoni, Gisbert Schneider. 2018

329 citations recorded by the source corpus.

Generative artificial intelligence offers a fresh view on molecular design. We present the first‐time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine‐tuned on recognizing retinoid X and peroxisome proliferator‐activated receptor agonists. We synthesized five top‐ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low‐micromolar receptor modulatory activity in cell‐based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry.

Subfields: Computational Theory and Mathematics, Molecular Biology, Pharmacology

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Citations in the corpus

Rethinking drug design in the artificial intelligence era (2019, methodology): “Nevertheless, pioneering prospective applications have shown that generative de novo design produces synthetically accessible molecules with desired properties and activities 75,76 .”
Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery (2018, unknown): “Several automated compound generators that use deep learning techniques have been made and have allowed automated analysis of generated compounds to obtain even better designs of compounds with desired properties and biological activity [216,217,231,232].”
The rise of artificial intelligence in healthcare applications (2020, background): “The identified compounds were synthesized and demonstrated potent receptor modulatory activity in in vitro assays [23].”
Artificial intelligence in drug discovery and development (2020, unknown): “80 Merk, D. et al. (2018) De novo design of bioactive small molecules by artificial”