title: Ensemble docking into flexible active sites. Critical evaluation of FlexE against JNK-3 and beta-secretase.
abstract: One of the main complicating factors in structure-based drug design is the conformational rearrangement of the receptor upon ligand binding implicating protein flexibility as a crucial component in virtual screening. The FlexE approach allows flexibility through discrete alternative conformations of varying parts of the protein taken from structures having similar backbone traces. Here the performance of FlexE was tested against that of FlexX and FlexX-Pharm, by carrying out virtual screening experiments on two sets of structurally distinct complexes, for the enzymes beta-secretase (BACE), and c-jun N-terminal kinase 3 (JNK-3). A large number of incompatible instances occurred between structural elements of the proteins thus loop movements could not be studied in JNK-3 as well as in BACE. The investigation of the side-chain flexibility revealed that at the most FlexE could achieve the enrichment yielded by FlexX in JNK-3 but not in BACE. Although limited side-chain variations (e.g. different protonation states) can be treated by FlexE, docking into protein ensembles remains a practical tool that decreases the average run time for a ligand.
authors.affiliation: CADD&HTS, Gedeon Richter Ltd., P.O. Box 27, H-1475 Budapest, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Polgár
authors.forename: György M
authors.initials: GM
authors.lastname: Keserü
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D001665:Binding Sites; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D048057:Mitogen-Activated Protein Kinase 10 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D048057:Mitogen-Activated Protein Kinase 10; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases