De Novo Design of Bioactive Small Molecules by Artificial Intelligence

作者：Daniel J. Merk, Lukas Friedrich, Francesca Grisoni, Gisbert Schneider · 发表于：Molecular Informatics · 年份：2018 · DOI：10.1002/minf.201700153 · 被引用次数：376 · 研究领域：Computational Drug Discovery Methods、Receptor Mechanisms and Signaling、Microbial Natural Products and Biosynthesis

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.