DeepFrag: a deep convolutional neural network for fragment-based lead optimization

Chem Sci. 2021 May 8;12(23):8036-8047. doi: 10.1039/d1sc00163a.


Machine learning has been increasingly applied to the field of computer-aided drug discovery in recent years, leading to notable advances in binding-affinity prediction, virtual screening, and QSAR. Surprisingly, it is less often applied to lead optimization, the process of identifying chemical fragments that might be added to a known ligand to improve its binding affinity. We here describe a deep convolutional neural network that predicts appropriate fragments given the structure of a receptor/ligand complex. In an independent benchmark of known ligands with missing (deleted) fragments, our DeepFrag model selected the known (correct) fragment from a set over 6500 about 58% of the time. Even when the known/correct fragment was not selected, the top fragment was often chemically similar and may well represent a valid substitution. We release our trained DeepFrag model and associated software under the terms of the Apache License, Version 2.0.