title: Interaction profiles of protein kinase-inhibitor complexes and their application to virtual screening.
abstract: A major challenge facing structure-based drug discovery efforts is how to leverage the massive amount of experimental (X-ray and NMR) and virtual structural information generated from drug discovery projects. Many important drug targets have large numbers of protein-inhibitor complexes, necessitating tools to compare and contrast their similarities and differences. This information would be valuable for understanding potency and selectivity of inhibitors and could be used to define target constraints to assist virtual screening. We describe a profile-based approach that enables us to capture the conservation of interactions between a set of protein-ligand receptor complexes. The use of profiles provides a sensitive means to compare multiple inhibitors binding to a drug target. We demonstrate the utility of profile-based analysis of small molecule complexes from the protein-kinase family to identify similarities and differences in binding of ATP, p38, and CDK2 compounds to kinases and how these profiles can be applied to differentiate the selectivity of these inhibitors. Importantly, our virtual screening results demonstrate superior enrichment of kinase inhibitors using profile-based methods relative to traditional scoring functions. Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets.
authors.affiliation: Computational Drug Design Group, Department of Research Informatics, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 01242, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.forename: Zhan
authors.initials: Z
authors.lastname: Deng
authors.forename: Juswinder
authors.initials: J
authors.lastname: Singh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D042846:CDC2-CDC28 Kinases / Q000737:chemistry / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D016208:Databases, Factual; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008958:Models, Molecular; D008962:Models, Theoretical; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases