Incorporating partial matches within multi-objective pharmacophore identification.
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.
Cottrell
Simon J
SJ
Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield, S1 4DP, UK.
Gillet
Valerie J
VJ
Taylor
Robin
R
D000465:Algorithms; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017076:Computer-Aided Design; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000187:drug effects; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular
D002257:Carbonic Anhydrase Inhibitors; D051357:Cyclin-Dependent Kinase 2; D024402:Carbonic Anhydrase II