Comparative Assessment of Scoring Functions on a Diverse Test Set

Abstract

Scoring functions are widely applied to the evaluation of protein-ligand binding in structure-based drug design. We have conducted a comparative assessment of 16 popular scoring functions implemented in main-stream commercial software or released by academic research groups. A set of 195 diverse protein-ligand complexes with high-resolution crystal structures and reliable binding constants were selected through a systematic nonredundant sampling of the PDBbind database and used as the primary test set in our study. All scoring functions were evaluated in three aspects, that is, "docking power", "ranking power", and "scoring power", and all evaluations were independent from the context of molecular docking or virtual screening. As for "docking power", six scoring functions, including GOLD::ASP, DS::PLP1, DrugScore(PDB), GlideScore-SP, DS::LigScore, and GOLD::ChemScore, achieved success rates over 70% when the acceptance cutoff was root-mean-square deviation < 2.0 A. Combining these scoring functions into consensus scoring schemes improved the success rates to 80% or even higher. As for "ranking power" and "scoring power", the top four scoring functions on the primary test set were X-Score, DrugScore(CSD), DS::PLP, and SYBYL::ChemScore. They were able to correctly rank the protein-ligand complexes containing the same type of protein with success rates around 50%. Correlation coefficients between the experimental binding constants and the binding scores computed by these scoring functions ranged from 0.545 to 0.644. Besides the primary test set, each scoring function was also tested on four additional test sets, each consisting of a certain number of protein-ligand complexes containing one particular type of protein. Our study serves as an updated benchmark for evaluating the general performance of today's scoring functions. Our results indicate that no single scoring function consistently outperforms others in all three aspects. Thus, it is important in practice to choose the appropriate scoring functions for different purposes.

Converting the Yeast Arginine Can1 Permease to a Lysine Permease

“…It is well known, however, that it is difficult to accurately predict experimental binding affinities using the scoring functions developed for docking programs and, albeit less difficult, to correlate docking scores with experimental binding affinities (56). A strategy for overcoming this limitation, which has been successfully applied to various targets (34 -37, 39), is to rescore the poses using the MM-GBSA method to calculate binding free energies (34).…”

Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties

“…The HotLig showed ∼85%-90% success rates for predicting ligand binding poses (12). On the other hand, the X-score was reported to be the best scoring function for ranking protein-ligand affinities while comparing with many other well-known scoring programs (25,26). Fig.…”

“…To investigate whether ZAA interrupts TLR4 signaling by competing the binding of LPS to MD-2, we applied an in silico molecular docking analysis to simulate the interactions between ZAA and MD-2. Previous studies have shown that knowledgebased scoring functions are better methods for prediction of protein-ligand interactions, whereas empirically based scoring functions are more effective for predicting ligand-binding affinities (25,26). Therefore, we used a new knowledge-based scoring program, HotLig, to predict the molecular interactions between ZAA and MD-2.…”

Public Domain Databases for Medicinal Chemistry

“…PDBbind (pdbbind.org.cn and pdbbind.org) [77][78][79] , like BindingMOAD above, collects measured affinities for many types of complexes in the PDB, including protein-small molecule, protein-protein, and nucleic acid-small molecule systems. The current version at pdbbind-org.cn provides about 8,000 data, of which about 6,000 are for protein-small molecule complexes, and is free for academic and commercial use, on acceptance of a license agreement.…”