期刊
COMPUTATIONAL BIOLOGY AND CHEMISTRY
卷 73, 期 -, 页码 179-188出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.compbiolchem.2018.02.004
关键词
SHP2; Allosteric inhibitors; SBP; CDOCKER; ADMET; Molecular dynamic simulation
资金
- Natural Science Foundations of China [81273361]
- Natural Science Foundation of Tianjin [16JCZDJC32500]
- International (Regional) Cooperation and Exchange Project of the National Natural Science Foundation of China [81611130090]
- Science & Technology Development Fund of Tianjin Education Commission for Higher Education [2017KJ229]
SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques. By means of molecular dynamics simulations, it was observed that these novel inhibitors not only had the same function as SHPO99 did in inhibiting SHP2, but also had more favorable conformation for binding to the receptor. Thus, this report may provide a new method in discovering novel and selective SHP2 allosteric inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.
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