title: Surrogate AutoShim: predocking into a universal ensemble kinase receptor for three dimensional activity prediction, very quickly, without a crystal structure.
abstract: "Ensemble surrogate AutoShim" is a kinase specific extension of the AutoShim docking method that solves the three traditional limitations of conventional docking: (1) it gives good correlations with affinity, (2) does not require a target protein structure, and (3) for a preprocessed company archive of 1.5 million compounds, is as fast as traditional 2D QSAR. It does require several hundred experimental IC 50 values for each new target. Original AutoShim adds pharmacophore "shims" to a crystal structure binding site. An iterative partial least squares (PLS) procedure selects the best pose, while adjusting the shim weights to reproduce IC 50 data. Surrogate AutoShim adjusts shims in one crystal structure to reproduce IC 50 data for a different kinase target. Ensemble surrogate AutoShim uses 16 structurally diverse kinase crystal structures as a "universal ensemble kinase receptor", suitable for any kinase target. The 1.5 million member Novartis screening collection has been predocked into the shimmed ensemble, so new kinase models can be built, and the entire corporate archive virtually screened, in hours rather than weeks. A kinase-biased set of 10,000 compounds, that samples the entire corporate archive, has been designed for lead discovery by iterative kinase screening.
authors.affiliation: Department of Computer Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA. eric.martin@novartis.com
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Martin
authors.forename: David C
authors.initials: DC
authors.lastname: Sullivan
mesh_terms: D008958:Models, Molecular; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D011494:Protein Kinases