BgN-Score and BsN-Score: bagging and boosting based ensemble neural networks scoring functions for accurate binding affinity prediction of protein-ligand complexes.
BACKGROUND
Accurately predicting the binding affinities of large sets of protein-ligand complexes is a key challenge in computational biomolecular science, with applications in drug discovery, chemical biology, and structural biology. Since a scoring function (SF) is used to score, rank, and identify drug leads, the fidelity with which it predicts the affinity of a ligand candidate for a protein's binding site has a significant bearing on the accuracy of virtual screening. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited predictive power has been a major roadblock toward cost-effective drug discovery. Therefore, in this work, we present novel SFs employing a large ensemble of neural networks (NN) in conjunction with a diverse set of physicochemical and geometrical features characterizing protein-ligand complexes to predict binding affinity.


RESULTS
We assess the scoring accuracies of two new ensemble NN SFs based on bagging (BgN-Score) and boosting (BsN-Score), as well as those of conventional SFs in the context of the 2007 PDBbind benchmark that encompasses a diverse set of high-quality protein families. We find that BgN-Score and BsN-Score have more than 25% better Pearson's correlation coefficient (0.804 and 0.816 vs. 0.644) between predicted and measured binding affinities compared to that achieved by a state-of-the-art conventional SF. In addition, these ensemble NN SFs are also at least 19% more accurate (0.804 and 0.816 vs. 0.675) than SFs based on a single neural network that has been traditionally used in drug discovery applications. We further find that ensemble models based on NNs surpass SFs based on the decision-tree ensemble technique Random Forests.


CONCLUSIONS
Ensemble neural networks SFs, BgN-Score and BsN-Score, are the most accurate in predicting binding affinity of protein-ligand complexes among the considered SFs. Moreover, their accuracies are even higher when they are used to predict binding affinities of protein-ligand complexes that are related to their training sets.
Hossam M
HM
Ashtawy
Nihar R
NR
Mahapatra
D000465:Algorithms; D001185:Artificial Intelligence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D008024:Ligands; D015233:Models, Statistical; D016571:Neural Networks, Computer; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
D008024:Ligands; D011506:Proteins