QM assisted ML for 19F NMR chemical shift prediction

Abstract

Ligand-observed 19 F NMR detection is an efficient method for screening libraries of fluorinated molecules in fragment-based drug design campaigns. Screening fluorinated molecules in large mixtures makes 19 F NMR a high-throughput method. Typically, these mixtures are generated from pools of well-characterized fragments. By predicting 19 F NMR chemical shift, mixtures could be generated for arbitrary fluorinated molecules facilitating for example focused screens. In a previous publication, we introduced a method to predict 19 F NMR chemical shift using rooted fluorine fingerprints and machine learning (ML) methods. Having observed that the quality of the prediction depends on similarity to the training set, we here propose to assist the prediction with quantum mechanics (QM) based methods in cases where compounds are not well covered by a training set. Beyond similarity, the performance of ML methods could be associated with individual features in compounds. A combination of both could be used as a procedure to split input data sets into those that could be predicted by ML and those that required QM processing. We could show on a proprietary fluorinated fragment library, known as LEF (Local Environment of Fluorine), and a public Enamine data set of 19 F NMR chemical shifts that ML and QM methods could synergize to outperform either method individually. Models built on Enamine data, as well as model building and QM workflow tools, can be found at https://github.com/PatrickPenner/lefshift and https://github.com/PatrickPenner/lefqm.