Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics. (April 2018)

• Record Type: Journal Article
• Authors: Jin, Wen-Yan; Ma, Ying; Li, Wei-Ya; Li, Hong-Lian; Wang, Run-Ling
• Is Part Of: Computational biology and chemistry. Volume 73(2018)
• Page Start: 179
• Page End: 188
• Publication Date: 2018-04
• Subjects: SPB structure based pharmacophore -- ADMET absorption, distribution, metabolism, excretion, and toxicity -- TCPTP T cell protein-tyrosinephosphatase -- PTP1B protein tyrosine phosphatase 1B -- NS Noonan Syndrome -- JMML juvenile myelomonocytic leukemia -- AML acutemyeloid leukemia -- SHP1 SH2 domain-containing phosphatase 1 -- Ras-ERK extracellular signal-related kinase -- GFA Genetic Function Approximation -- ROC receiver operating characteristic -- HBD hydrogenbond donors -- HBA hydrogen bond acceptors -- AUC area under ROC curve -- HIA human intestinal absorption -- BBB blood-brain barrier -- PPB plasma protein binding -- MD molecular dynamics -- NVT constant Number of Particles, Volume, and Temperature -- NPT Temperature and constant Number of particles Pressure, and Temperature -- Hyd hydrophobic -- PI positive ionizable; SHP2 -- Allosteric inhibitors -- SBP -- CDOCKER -- ADMET -- Molecular dynamic simulation; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2018.02.004
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: The technique of "Receptor-Ligand Pharmacophore" was used to build the pharmacophore model. 7 potential SHP2 inhibitors were discovered by pharmcophore-based virtual screening and docking analysis. Compared with the SHP099, seven compounds had better conformation in binding to SHP2 in both Docking and Dynamics simulations. 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.