Search

Your search keyword '"Ma, Yang-Chun"' showing total 15 results
Start Over Author "Ma, Yang-Chun" Publication Year Range Last 50 years
15 results on '"Ma, Yang-Chun"'

4. Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition

Author

Zhou Liang, Wang Run-ling, Yang Wenyu, Du Shan, Wu JingWei, Li LiPeng, Ma Ying, Li Wei-Ya, and Ma Yang-Chun

Subjects
Chemistry, Organic Chemistry, Allosteric regulation, A protein, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Tyrosine phosphorylation, General Medicine, Protein tyrosine phosphatase, Molecular Dynamics Simulation, Catalysis, Inorganic Chemistry, chemistry.chemical_compound, Allosteric Regulation, Neoplasms, Drug Discovery, Biophysics, Humans, Physical and Theoretical Chemistry, Molecular Biology, Allosteric Site, Information Systems
Abstract

SHP2 is a protein tyrosine phosphatase (PTP) that can regulate the tyrosine phosphorylation level. Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are inhibitors of SHP2 and bind to different allosteric sites 1 and 2, respectively. Studies have shown that combining SHP099 with SHP844 will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamic simulations to explore the dual allosteric targeted inhibition mechanism. The result shows that the residues THR108-TRP112 (allosteric site 1) move to LEU236-GLN245 (αB-αC link loop in PTP domain) , the residues of GLN79-GLN87 (allosteric site 2) get close to LEU262-GLN269 (αA-αB link loop in PTP domain) and HIS458-ARG465 (P-loop) come near to ARG501-THR507 (Q-loop) in SHP2-SHP099-SHP844 system, which makes the "inactive conformation" more stable and prevents the substrate from entering the catalytic site. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2.

Published
2021

10. Exploring the cause of the inhibitor 4AX attaching to binding site disrupting protein tyrosine phosphatase 4A1 trimerization by molecular dynamic simulation

Author

Lu Xin-Hua, Duan Yuqing, Li Wei-Ya, Run-Ling Wang, Ma Ying, and Ma Yang-Chun

Subjects
Protein Conformation, alpha-Helical, 030303 biophysics, Motility, Trimer, Cell Cycle Proteins, Protein tyrosine phosphatase, Molecular Dynamics Simulation, Ligands, 03 medical and health sciences, Molecular dynamics, Motion, Protein Domains, Structural Biology, Molecule, Humans, Binding site, Enzyme Inhibitors, Molecular Biology, 0303 health sciences, Binding Sites, Chemistry, Cell growth, Membrane Proteins, General Medicine, Molecular Docking Simulation, Docking (molecular), Biophysics, Thermodynamics, Protein Conformation, beta-Strand, Protein Multimerization, Protein Tyrosine Phosphatases
Abstract

Ectopic overexpression of protein tyrosine phosphatase of liver regeneration-1 (PTP4A1, also called PRL-1) markedly enhanced hepatocellular carcinoma (HCC) cells migration and invasion. The PTP4A1 trimerization played a vital role in mediating cell proliferation and motility. Biochemical and structural studies have proved that the compound 4AX, a well-known inhibitor for PRL1, directly binds to the PTP4A1 trimer interface and obstructs trimer formation of PTP4A1. However, the molecular basis of the ligand-4AX inhibition on PTP4A1 trimer conformations remains unclear. In this study, the docking analysis and the molecular dynamics simulation (MD simulation) study were performed to investigate how the molecule binding at each interface disrupted the trimer formation. The results suggested that the ligand-4AX attaching to the binding site changed the conformation of A:Q131, A:Q135 in the AC interface, C:R18, C:P96 in the CA interface and B:Q131 in the BA interface, leading to the weak interactions between subunits and thus resulting in the disruption of the PTP4A1 trimerization.

Published
2019
Full Text
View/download PDF

11. Exploring the dynamic mechanism of allosteric drug SHP099 inhibiting SHP2E69K.

Author

Du, Shan, Lu, Xin-hua, Li, Wei-Ya, Li, Li-Peng, Ma, Yang-Chun, Zhou, Liang, Wu, Jing-Wei, Ma, Ying, and Wang, Run-Ling

Abstract

The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

12. Identification of novel inhibitor of protein tyrosine phosphatases delta: structure-based pharmacophore modeling, virtual screening, flexible docking, molecular dynamics simulation, and post-molecular dynamics analysis

Author

Ma, Yang-Chun, primary, Yang, Bing, additional, Wang, Xin, additional, Zhou, Liang, additional, Li, Wei-Ya, additional, Liu, Wen-Shan, additional, Lu, Xin-Hua, additional, Zheng, Zhi-Hui, additional, Ma, Ying, additional, and Wang, Run-Ling, additional

Published
2019
Full Text
View/download PDF

15. Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5 H )-furanone Derivatives as Potent Quorum Sensing Inhibitors.

Author

Zhang P, Chen W, Ma YC, Bai B, Sun G, Zhang S, Chang X, Wang Y, Jiang N, Zhang X, and Ma S

Subjects
Animals, Mice, Anti-Bacterial Agents pharmacology, Virulence Factors, Ciprofloxacin pharmacology, Pseudomonas aeruginosa, Biofilms, Quorum Sensing, Furans pharmacology, Furans therapeutic use
Abstract

Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4-fluorophenyl-5-methylene-2(5 H )-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro . What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and β-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa . As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results