Knowledge-based scoring functions in drug design. 1. Developing a target-specific method for kinase-ligand interactions

J Chem Inf Model. 2010 Aug 23;50(8):1378-86. doi: 10.1021/ci100182c.

Abstract

Protein kinases are attractive targets for therapeutic interventions in many diseases. Due to their importance in drug discovery, a kinase family-specific potential of mean force (PMF) scoring function, kinase-PMF, was developed to assess the binding of ATP-competitive kinase inhibitors. It is hypothesized that target-specific PMF scoring functions may achieve increased performance in scoring along with the growth of the PDB database. The kinase-PMF inherits the functions and atom types in PMF04 and uses a kinase data set of 872 complexes to derive the potentials. The performance of kinase-PMF was evaluated with an external test set containing 128 kinase crystal structures. We compared it with eight scoring functions commonly used in computer-aided drug design, either in terms of the retrieval rate of retrieving "right" conformations or a virtual screening study. The evaluation results clearly demonstrate that a target-specific scoring function is a promising way to improve prediction power in structure-based drug design compared with other general scoring functions. To provide this rescoring service for researchers, a publicly accessible Web site was established at http://202.127.30.184:8080/scoring/index.jsp .

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Drug Design*
  • Ligands
  • Molecular Conformation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Protein Kinases