Improving ΔΔG Predictions with a Multitask Convolutional Siamese Network

The lead optimization phase of drug discovery refines an initial hit molecule for desired properties, especially potency. Synthesis and experimental testing of the small perturbations during this refinement can be quite costly and time-consuming. Relative binding free energy (RBFE, also referred to as Delta Delta G) methods allow the estimation of binding free energy changes after small changes to a ligand scaffold. Here, we propose and evaluate a Siamese convolutional neural network (CNN) for the prediction of RBFE between two bound ligands. We show that our multitask loss is able to improve on a previous state-of-the-art Siamese network for RBFE prediction via increased regularization of the latent space. The Siamese network architecture is well suited to the prediction of RBFE in comparison to a standard CNN trained on the same data (Pearson's R of 0.553 and 0.5, respectively). When evaluated on a left-out protein family, our Siamese CNN shows variability in its RBFE predictive performance depending on the protein family being evaluated (Pearson's R ranging from -0.44 to 0.97). RBFE prediction performance can be improved during generalization by injecting only a few examples (few-shot learning) from the evaluation data set during model training.

Automated summary

In this study, a Siamese convolutional neural network (CNN) is proposed for the prediction of relative binding free energy (RBFE) between two bound ligands. The network shows improved performance in RBFE prediction compared to a standard CNN, and its predictive performance varies among different protein families. Additionally, the RBFE prediction performance can be enhanced through few-shot learning during model training.