Multiobjective optimization of pharmacophore hypotheses: bias toward low-energy conformations.
Two methods are described for biasing conformational search during pharmacophore elucidation using a multiobjective genetic algorithm (MOGA). The MOGA explores conformation on-the-fly while simultaneously aligning a set of molecules such that their pharmacophoric features are maximally overlaid. By using a clique detection method to generate overlays of precomputed conformations to initialize the population (rather than starting from random), the speed of the algorithm has been increased by 2 orders of magnitude. This increase in speed has enabled the program to be applied to greater numbers of molecules than was previously possible. Furthermore, it was found that biasing the conformations explored during search time to those found in the Cambridge Structural Database could also improve the quality of the results.
Gardiner
Eleanor J
EJ
Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield S1 4DP, United Kingdom. e.gardiner@sheffield.ac.uk
Cosgrove
David A
DA
Taylor
Robin
R
Gillet
Valerie J
VJ
D000465:Algorithms; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
D004791:Enzyme Inhibitors; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase; D051357:Cyclin-Dependent Kinase 2; D013917:Thrombin