Full Paper

Molecular modeling annual

, Volume 4, Issue 12, pp 379-394

First online:

SCORE: A New Empirical Method for Estimating the Binding Affinity of a Protein-Ligand Complex

  • Renxiao WangAffiliated withInstitute of Physical Chemistry, Peking University, Beijing 100871, P.R.China. Tel: +86-10-62751490; Fax:   +86-10-62751725. E-mail: lai@ipc.pku.edu.cn
  • , Liang LiuAffiliated withInstitute of Physical Chemistry, Peking University, Beijing 100871, P.R.China. Tel: +86-10-62751490; Fax:   +86-10-62751725. E-mail: lai@ipc.pku.edu.cn
  • , Luhua LaiAffiliated withInstitute of Physical Chemistry, Peking University, Beijing 100871, P.R.China. Tel: +86-10-62751490; Fax:   +86-10-62751725. E-mail: lai@ipc.pku.edu.cn
  • , Youqi TangAffiliated withInstitute of Physical Chemistry, Peking University, Beijing 100871, P.R.China. Tel: +86-10-62751490; Fax:   +86-10-62751725. E-mail: lai@ipc.pku.edu.cn

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Abstract

A new method is presented to estimate the binding affinity of a protein-ligand complex with known three-dimensional structure. The method, SCORE, uses an empirical scoring function to describe the binding free energy, which includes terms to account for van der Waals contact, metal-ligand bonding, hydrogen bonding, desolvation effect, and deformation penalty upon the binding process. The coefficients of each term are obtained by multivariate regressional analysis of a diverse training set of 170 protein-ligand complexes. The final scoring function reproduces the binding free energies of the whole training set with a cross-validated deviation of 6.3 kJ/mol. The predictive ability of the function is further tested by a set of 11 endothiapepsin complexes and the internal consistency of the function is demonstrated in a stepwise procedure named Evolutionary Test. A major innovation of this method is the introduction of an atomic binding score which allows the researcher to inspect and optimize the lead compound rationally in a structure-based drug design scheme.

Keywords Protein-ligand complex Binding affinity Empirical scoring function Structure-based drug design