Theoretical and Computational Chemistry

Learning from the Ligand: Using Ligand-Based Features to Improve Binding Affinity Prediction



Machine learning scoring functions for protein-ligand binding affinity prediction have been found to consistently outperform classical scoring functions. Structure-based scoring functions for universal affinity prediction typically use features describing interactions derived from the protein-ligand complex, with limited information about the chemical or topological properties of the ligand itself. We demonstrate that the performance of machine learning scoring functions are consistently improved by the inclusion of diverse ligand-based features. For example, a Random Forest combining the features of RF-Score v3 with RDKit molecular descriptors achieved Pearson correlation coefficients of up to 0.831, 0.785, and 0.821 on the PDBbind 2007, 2013, and 2016 core sets respectively, compared to 0.790, 0.737, and 0.797 when using the features of RF-Score v3 alone. Excluding proteins and/or ligands that are similar to those in the test sets from the training set has a significant effect on scoring function performance, but does not remove the predictive power of ligand-based features. Furthermore a Random Forest using only ligand-based features is predictive at a level similar to classical scoring functions and it appears to be predicting the mean binding affinity of a ligand for its protein targets.


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Supplementary material

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