Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model

TitleDiscovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model
Publication TypeJournal Article
Year of Publication2008
AuthorsKolb P., Huang D., Dey F., Caflisch A.
JournalJournal of Medicinal Chemistry
Volume51
Issue5
Pagination1179-1188
Date Published2008 Mar 13
Type of ArticleResearch Article
ISSN0022-2623
KeywordsHumans, Models, Molecular, Protein Binding, Protein Kinase Inhibitors, Protein Kinases, Quantitative Structure-Activity Relationship, Static Electricity, Thermodynamics
Abstract

The linear interaction energy method with continuum electrostatics (LIECE) is evaluated in depth on five kinases. The two multiplicative coefficients for the van der Waals energy and electrostatic free energy are shown to be transferable among different kinases. Moreover, good enrichment factors are obtained for a library of 40375 diverse compounds seeded with 73 known inhibitors of CDK2. Therefore, a general two-parameter LIECE model for kinases is derived by combining large data sets of inhibitors of CDK2, Lck, and p38. This two-parameter model is cross-validated on two kinases not used for fitting; it shows an average error of about 1.5 kcal/mol for the prediction of absolute binding affinity of 37 and 128 known inhibitors of EphB4 and EGFR, respectively. High-throughput docking and ranking by two-parameter LIECE models are shown to be able to identify novel low-μM EphB4 and CDK2 inhibitors of low-molecular weight (≤ 355 g/mol).

DOI10.1021/jm070654j
pubindex

0095

Alternate JournalJ. Med. Chem.
PubMed ID18271520
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