title: Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms.
abstract: We examined the quality of Catalyst's conformational model generation algorithm via a large scale study based on the crystal structures of a sample of 510 pharmaceutically relevant protein-ligand complexes extracted from the Protein Data Bank (PDB). Our results show that the tested algorithms implemented within Catalyst are able to produce high quality conformers, which in most of the cases are well suited for in silico drug research. Catalyst-specific settings were analyzed, such as the method used for the conformational model generation (FAST vs BEST) and the maximum number of generated conformers. By setting these options for higher fitting quality, the average RMS values describing the similarity of experimental and simulated conformers were improved from an RMS of 1.06 with max. 50 FAST generated conformers to an RMS of 0.93 with max. 255 BEST generated conformers, which represents an improvement by 12%. Each method provides best fitting conformers with an RMS value<1.50 in more than 80% of all cases. We analyzed the computing time/quality ratio of various conformational model generation settings and examined ligands in high energy conformations. Furthermore, properties of the same ligands in various proteins were investigated, and the fitting qualities of experimental conformations from the PDB and the Cambridge Structural Database (CSD) were compared. One of the most important conclusions of former studies, the fact that bioactive conformers often have energy high above that of global minima, was confirmed.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
mesh_terms: D000465:Algorithms; D002384:Catalysis; D003201:Computers; D030562:Databases, Protein; D008024:Ligands; D008968:Molecular Conformation; D008970:Molecular Weight; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013449:Sulfonamides
chemical_list: D008024:Ligands; D011506:Proteins; D013449:Sulfonamides