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Perspectives in Drug Discovery and Design

, Volume 20, Issue 1, pp 99–114 | Cite as

A knowledge-based scoring function for protein-ligand interactions: Probing the reference state

  • Ingo Muegge
Article

Abstract

Knowledge-based scoring functions have recently emerged as an alternative and very promising way of ranking protein-ligand complexes with known 3D structure according to their binding affinities. Theses implified potential-based approaches use the structural information stored in databases of protein-ligand complexes to derive atom pair interaction potentials also known as potentials of mean force (PMF). The derived PMF depend on the definition of a suitable reference state. The reference states vary among suggested knowledge-based scoring functions. Therefore, we attempt here to shed some light on the influence of different reference state definitions on the predictive power of a knowledge-based scoring function that has been introduced by us very recently [J. Med. Chem., 42 (1999) 791]. It is shown that a reference state that implicitly and more comprehensively accounts for protein and ligand solvation gives the most consistent scoring results for four test sets of diverse protein-ligand complexes taken from the Brookhaven Protein Data Bank. It is also shown that a reference sphere radius of at least 7–8 Å is needed to effectively capture solvation effects that are treated implicitly in the scoring function.

Helmholtz free energy PMF scoring protein-ligand binding reference state 

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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Ingo Muegge
    • 1
  1. 1.Bayer Research CenterWest HavenU.S.A.

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