Article,
Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model
J. Med. Chem., 51 (5): 1179-1188 (March 2008)
DOI: {10.1021/jm070654j}
Abstract
The linear interaction energy method with continuum electrostatics
(LIEGE) 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 LIEGE 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
LIEGE models are shown to be able to identify novel low-micromolar
EphB4 and CDK2 inhibitors of low-molecular weight (<= 355 g/mol).
