Linked Life Data

11327774

Source:http://linkedlifedata.com/resource/pubmed/id/11327774

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-4-30
pubmed:abstractText
Side-chain or even backbone adjustments upon docking of different ligands to the same protein structure, a phenomenon known as induced fit, are frequently observed. Sometimes point mutations within the active site influence the ligand binding of proteins. Furthermore, for homology derived protein structures there are often ambiguities in side-chain placement and uncertainties in loop modeling which may be critical for docking applications. Nevertheless, only very few molecular docking approaches have taken into account such variations in protein structures. We present the new software tool FlexE which addresses the problem of protein structure variations during docking calculations. FlexE can dock flexible ligands into an ensemble of protein structures which represents the flexibility, point mutations, or alternative models of a protein. The FlexE approach is based on a united protein description generated from the superimposed structures of the ensemble. For varying parts of the protein, discrete alternative conformations are explicitly taken into account, which can be combinatorially joined to create new valid protein structures.FlexE was evaluated using ten protein structure ensembles containing 105 crystal structures from the PDB and one modeled structure with 60 ligands in total. For 50 ligands (83 %) FlexE finds a placement with an RMSD to the crystal structure below 2.0 A. In all cases our results are of similar quality to the best solution obtained by sequentially docking the ligands into all protein structures (cross docking). In most cases the computing time is significantly lower than the accumulated run times for the single structures. FlexE takes about five and a half minutes on average for placing one ligand into the united protein description on a common workstation. The example of the aldose reductase demonstrates the necessity of considering protein structure variations for docking calculations. We docked three potent inhibitors into four protein structures with substantial conformational changes within the active site. Using only one rigid protein structure for screening would have missed potential inhibitors whereas all inhibitors can be docked taking all protein structures into account.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2836
pubmed:author
pubmed:copyrightInfo
Copyright 2001 Academic Press.
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
308
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
377-95
pubmed:dateRevised
2009-11-3
pubmed:meshHeading
pubmed-meshheading:11327774-Aldehyde Reductase, pubmed-meshheading:11327774-Algorithms, pubmed-meshheading:11327774-Animals, pubmed-meshheading:11327774-Binding Sites, pubmed-meshheading:11327774-Computer Simulation, pubmed-meshheading:11327774-Crystallography, X-Ray, pubmed-meshheading:11327774-Drug Design, pubmed-meshheading:11327774-Enzyme Inhibitors, pubmed-meshheading:11327774-Folic Acid, pubmed-meshheading:11327774-Folic Acid Antagonists, pubmed-meshheading:11327774-Humans, pubmed-meshheading:11327774-Internet, pubmed-meshheading:11327774-Ligands, pubmed-meshheading:11327774-Methotrexate, pubmed-meshheading:11327774-Models, Molecular, pubmed-meshheading:11327774-Pliability, pubmed-meshheading:11327774-Point Mutation, pubmed-meshheading:11327774-Protein Binding, pubmed-meshheading:11327774-Protein Conformation, pubmed-meshheading:11327774-Proteins, pubmed-meshheading:11327774-Software, pubmed-meshheading:11327774-Tetrahydrofolate Dehydrogenase, pubmed-meshheading:11327774-Time Factors
pubmed:year
2001
pubmed:articleTitle
FlexE: efficient molecular docking considering protein structure variations.
pubmed:affiliation
German National Research Center for Information Technology (GMD), Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, 53754 Sankt Augustin, Germany. Holger.Claussen@gmd.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't