Drug Analogs from Fragment-Based Long Short-Term Memory Generative Neural Networks

Awale, Mahendra; Sirockin, Finton; Stiefl, Nikolaus; Reymond, Jean-Louis (2019). Drug Analogs from Fragment-Based Long Short-Term Memory Generative Neural Networks. Journal of chemical information and modeling, 59(4), pp. 1347-1356. American Chemical Society 10.1021/acs.jcim.8b00902

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Several recent reports have shown that long short-term memory generative neural networks (LSTM) of the type used for grammar learning efficiently learn to write Simplified Molecular Input Line Entry System (SMILES) of druglike compounds when trained with SMILES from a database of bioactive compounds such as ChEMBL and can later produce focused sets upon transfer learning with compounds of specific bioactivity profiles. Here we trained an LSTM using molecules taken either from ChEMBL, DrugBank, commercially available fragments, or from FDB-17 (a database of fragments up to 17 atoms) and performed transfer learning to a single known drug to obtain new analogs of this drug. We found that this approach readily generates hundreds of relevant and diverse new drug analogs and works best with training sets of around 40,000 compounds as simple as commercial fragments. These data suggest that fragment-based LSTM offer a promising method for new molecule generation.

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