Generation of multiple pharmacophore hypotheses using multiobjective optimisation techniques.
Pharmacophore methods provide a way of establishing a structure activity relationship for a series of known active ligands. Often, there are several plausible hypotheses that could explain the same set of ligands and, in such cases, it is important that the chemist is presented with alternatives that can be tested with different synthetic compounds. Existing pharmacophore methods involve either generating an ensemble of conformers and considering each conformer of each ligand in turn or exploring conformational space on-the-fly. The ensemble methods tend to produce a large number of hypotheses and require considerable effort to analyse the results, whereas methods that vary conformation on-the-fly typically generate a single solution that represents one possible hypothesis, even though several might exist. We describe a new method for generating multiple pharmacophore hypotheses with full conformational flexibility being explored on-the-fly. The method is based on multiobjective evolutionary algorithm techniques and is designed to search for an ensemble of diverse yet plausible overlays which can then be presented to the chemist for further investigation.
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
Wilton
David J
DJ
D000465:Algorithms; D001665:Binding Sites; D017076:Computer-Aided Design; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D006836:Hydro-Lyases; C082741:scytalone dehydratase