Incorporating partial matches within multi-objective pharmacophore identification

J Comput Aided Mol Des. 2006 Dec;20(12):735-49. doi: 10.1007/s10822-006-9086-7. Epub 2007 Jan 4.

Abstract

This paper describes the extension of our earlier multi-objective method for generating plausible pharmacophore hypotheses to incorporate partial matches. Diverse sets of molecules rarely adopt exactly the same binding mode, and so allowing the identification of partial matches allows our program to be applied to larger and more diverse datasets. The method explores the conformational space of a series of ligands simultaneously with their alignment using a multi-objective genetic algorithm (MOGA). The principles of Pareto ranking are used to evolve a diverse set of pharmacophore hypotheses that are optimised on conformational energy of the ligands, the goodness of the overlay and the volume of the overlay. A partial match is defined as a pharmacophoric feature that is present in at least two, but not all, of the ligands in the set. The number of ligands that map to a given pharmacophore point is taken into account when evaluating an overlay. The method is applied to a number of test cases extracted from the Protein Data Bank (PDB) where the true overlay is known.

MeSH terms

  • Algorithms
  • Binding Sites
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Computer-Aided Design
  • Cyclin-Dependent Kinase 2 / chemistry
  • Cyclin-Dependent Kinase 2 / drug effects
  • Databases, Protein
  • Drug Design*
  • Humans
  • In Vitro Techniques
  • Models, Molecular

Substances

  • Carbonic Anhydrase Inhibitors
  • Cyclin-Dependent Kinase 2
  • Carbonic Anhydrase II