DLIGAND2: an improved knowledge-based energy function for protein–ligand interactions using the distance-scaled, finite, ideal-gas reference state

Performance of structure-based molecular docking largely depends on the accuracy of scoring functions. One important type of scoring functions are knowledge-based potentials derived from known three-dimensional structures of proteins and/or protein–ligand complex structures. This study seeks to improve a knowledge-based protein–ligand potential based on a distance-scale finite ideal-gas reference (DFIRE) state (DLIGAND) by expanding the representation of protein atoms from 13 mol2 atom types to 167 residue-specific atom types, and employing a recently updated dataset containing 12,450 monomer protein chains for training. We found that the updated version DLIGAND2 has a consistent improvement over DLIGAND in predicting binding affinities for either native complex structures or docking-generated poses. More importantly, DLIGAND2 has a 52% increase over DLIGAND in enrichment factors in top 1% predictions based on the DUD-E decoy set, and consistently improves over Autodock Vina and other statistical energy functions in all three benchmark tests. We further found that DLIGAND2 outperforms empirical and machine-learning methods compared for virtual screening on new targets that are not homologous to the DUD-E training set. Given the best performance as a parameter-free statistical potential and among the best in all performance measures, DLIGAND2 should be useful for re-assessing the poses generated by docking software, or acting as one term in other scoring functions. The program is available at https://github.com/sysu-yanglab/DLIGAND2. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13321-019-0373-4) contains supplementary material, which is available to authorized users.