TY - JOUR KW - Models, Molecular KW - Thermodynamics KW - Humans KW - Protein Binding KW - Static Electricity KW - Protein Kinases KW - Quantitative Structure-Activity Relationship KW - Protein Kinase Inhibitors AU - P. Kolb AU - D. Huang AU - F. Dey AU - A. Caflisch AB -

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).

BT - Journal of Medicinal Chemistry C1 - 0095 DA - 2008 Mar 13 DO - 10.1021/jm070654j IS - 5 J2 - J. Med. Chem. LA - eng M3 - Research Article N2 -

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).

PY - 2008 SP - 1179 EP - 1188 T2 - Journal of Medicinal Chemistry TI - Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model VL - 51 SN - 0022-2623 ER -