Druggability Indices for Protein Targets Derived from NMR-Based Screening Data

• Published in: Journal of medicinal chemistry 2005-04, Vol.48 (7), p.2518-2525
• Main Authors: Hajduk, Philip J, Huth, Jeffrey R, Fesik, Stephen W
• Format: Article
• Language: English
• Subjects: Algorithms; Binding Sites; Biological and medical sciences; Databases, Factual; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Models, Molecular; Pharmaceutical Preparations - chemistry; Pharmacology. Drug treatments; Proteins - chemistry; Quantitative Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049131r

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 R 2 of 0.72, an adjusted R 2 of 0.65, and a leave-one-out Q 2 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.