Automated docking of highly flexible ligands by genetic algorithms: a critical assessment.
An improved version of the fragment-based flexible ligand docking approach SEED-FFLD is tested on inhibitors of human immunodeficiency virus type 1 protease, human alpha-thrombin and the estrogen receptor beta. The docking results indicate that it is possible to correctly reproduce the binding mode of inhibitors with more than ten rotatable bonds if the strain in their covalent geometry upon binding is not large. A high degree of convergence towards a unique binding mode in multiple runs of the genetic algorithm is proposed as a necessary condition for successful docking.
Cecchini
Marco
M
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Kolb
Peter
P
Majeux
Nicolas
N
Caflisch
Amedeo
A
D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D047629:Estrogen Receptor beta; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry*
D047629:Estrogen Receptor beta; D017320:HIV Protease Inhibitors; D008024:Ligands; D011960:Receptors, Estrogen; D013917:Thrombin