Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics

Computational Biology and Chemistry
Wen-Yan JinRun-Ling Wang

Abstract

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 SHP099 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.

Citations

Feb 10, 2019·International Journal of Molecular Sciences·Shaoming JinPengjie Wang
May 28, 2019·Journal of Cellular Biochemistry·Wen-Shan LiuRun-Ling Wang
Nov 17, 2020·Chemical Biology & Drug Design·Rati Kailash Prasad Tripathi, Senthil Raja Ayyannan
Jan 29, 2019·Journal of Medicinal Chemistry·Jeffrey T BagdanoffMatthew J LaMarche

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