Druggability Indices for Protein Targets Derived from NMR-Based Screening Data
Top Cited Papers
- 24 February 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (7) , 2518-2525
- https://doi.org/10.1021/jm049131r
Abstract
An analysis of heteronuclear-NMR-based screening data is used to derive relationships between the ability of small molecules to bind to a protein and various parameters that describe the protein binding site. It is found that a simple model including terms for polar and apolar surface area, surface complexity, and pocket dimensions accurately predicts the experimental screening hit rates with an R2 of 0.72, an adjusted R2 of 0.65, and a leave-one-out Q2 of 0.56. Application of the model to predict the druggability of protein targets not used in the training set correctly classified 94% of the proteins for which high-affinity, noncovalent, druglike leads have been reported. In addition to understanding the pocket characteristics that contribute to high-affinity binding, the relationships that have been defined allow for quantitative comparative analyses of protein binding sites for use in target assessment and validation, virtual ligand screening, and structure-based drug design.Keywords
This publication has 22 references indexed in Scilit:
- SOS-NMR: A Saturation Transfer NMR-Based Method for Determining the Structures of Protein−Ligand ComplexesJournal of the American Chemical Society, 2004
- Searching for functional sites in protein structuresCurrent Opinion in Chemical Biology, 2004
- Identification of Protein–Protein Interaction Sites from Docking Energy LandscapesJournal of Molecular Biology, 2003
- Protein surface roughness and small molecular binding sitesJournal of Molecular Biology, 1999
- Anatomy of hot spots in protein interfacesJournal of Molecular Biology, 1998
- NMR-Based Discovery of Lead Inhibitors That Block DNA Binding of the Human Papillomavirus E2 ProteinJournal of Medicinal Chemistry, 1997
- Automatic identification and representation of protein binding sites for molecular dockingProtein Science, 1997
- Organic solvents identify specific ligand binding sites on protein surfacesNature Biotechnology, 1997
- Discovering High-Affinity Ligands for Proteins: SAR by NMRScience, 1996
- The Automatic Search for Ligand Binding Sites in Proteins of Known Three-dimensional Structure Using only Geometric CriteriaJournal of Molecular Biology, 1996