期刊
CHEMMEDCHEM
卷 5, 期 7, 页码 1007-1014出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201000085
关键词
gatekeepers; high-throughput screening; inhibitors; kinases; quantum mechanics
资金
- Swiss National Science Foundation
A procedure based on semi-empirical quantum mechanical (QM) calculations of interaction energy is proposed for the rapid screening of compound poses generated by high throughput docking. Small molecules (consisting of 2-10 atoms and termed probes) are overlapped with polar groups in the binding site of the protein target. The interaction energy values between each compound pose and the probes, calculated by a semi empirical Hamiltonian, are used as filters. The QM probe method does not require fixed partial charges and takes into account polarization and charge-transfer effects which are not captured by conventional force fields. The procedure is applied to screen similar to 100 million poses (of 2.7 million commercially available compounds) obtained by high-throughput docking in the ATP binding site of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4). Three QM probes on the hinge region and one at the entrance pocket are employed to select for binding affinity, while a QM probe on the side chain of the so-called gatekeeper residue (a hypervariable residue in the kinome) is used to enforce selectivity. The poses with favorable interactions with the five QM probes are filtered further for hydrophobic matching and low ligand strain. In this way, a single-digit micromolar inhibitor of EphB4 with a relatively good selectivity profile is identified in a multimillion-compound library upon experimental tests of only 23 molecules.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据