Scoring confidence index: statistical evaluation of ligand binding mode predictions

  • Maria I. Zavodszky
  • Andrew W. Stumpff-Kane
  • David J. Lee
  • Michael Feig
Warr's Piece

DOI: 10.1007/s10822-008-9258-8

Cite this article as:
Zavodszky, M.I., Stumpff-Kane, A.W., Lee, D.J. et al. J Comput Aided Mol Des (2009) 23: 289. doi:10.1007/s10822-008-9258-8

Abstract

Protein-ligand docking programs can generate a large number of possible binding orientations for each ligand candidate. The challenge is to identify the orientations closest to the native binding mode using a scoring method. Many different scoring functions have been developed for protein-ligand scoring, but their performance on binding mode prediction is often target-dependent. In this study, a statistical approach was employed to provide a confidence measure of scoring performance in finding close to the correct docked ligand orientations. It exploits the fact that the scores provided by an adequately performing scoring function generally improve as the ligand binding modes get closer to the correct native orientation. For such cases, the correlation coefficient of scores versus distances is expected to be highest when the most native-like orientation is used as a reference. This correlation coefficient, called the correlation-based score (CBScore), was used as an indicator of how far the docked pose was from the native orientation. The correlation between the original scores and CBScores as well as the range of CBScores were found to be good measures of scoring performance. They were combined into a single quantity, called the scoring confidence index. High values of the scoring confidence index were indicative of pronounced and relatively smooth binding energy landscapes with easily discernable global minima, resulting in reliable binding mode predictions. Low values of this index reflected rugged energy landscapes making the prediction of the correct binding mode very difficult and often unreliable. The diagnostic ability of the scoring confidence index was tested on a non-redundant set of 50 protein-ligand complexes scored with three commonly employed scoring functions: AffiScore, DrugScore and X-Score. Binding mode predictions were found to be three times more reliable for complexes with scoring confidence indices in the upper half than for cases with values in the lower half of the resulting range of 0–1.6. This new confidence measure of scoring performance is expected to be a valuable tool for virtual screening applications.

Keywords

Binding orientation Correlation-based score Energy landscape Protein-ligand docking Scoring function 

Abbreviations

CBScore

Correlation-based score

PDB

Protein Data Bank

RMSD

Root-mean-square deviation

PSR

Pseudo-RMSD

SCI

Scoring confidence index

Supplementary material

10822_2008_9258_MOESM_ESM.doc (688 kb)
(DOC 687 kb)

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Maria I. Zavodszky
    • 1
    • 2
  • Andrew W. Stumpff-Kane
    • 1
  • David J. Lee
    • 3
  • Michael Feig
    • 1
    • 2
    • 4
  1. 1.Department of Biochemistry and Molecular BiologyMichigan State UniversityEast LansingUSA
  2. 2.Quantitative Biology InitiativeMichigan State UniversityEast LansingUSA
  3. 3.Lyman Briggs CollegeMichigan State UniversityEast LansingUSA
  4. 4.Department of ChemistryMichigan State UniversityEast LansingUSA

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