Temporal trends of transcatheter aortic valve replacement outcomes in a high-volume center from China.

Since the first transcatheter aortic valve replacement (TAVR) was performed in China in 2010, TAVR has developed rapidly. However, the temporal trends in the 1-year prognosis after TAVR in China have not been described. This study enrolled patients treated at a high-volume Chinese TAVR center, West China Hospital, between 2015 and 2022, to analyze and characterize the temporal trends in 1-year outcomes.

Surface Engineering and Programmed Self-Assembly of Silica Nanoparticles with Controllable Polystyrene/Poly(4-vinybenzyl azide) Patches.

The programmed self-assembly of patchy nanoparticles (NPs) through a bottom-up approach is an efficient strategy for producing highly organized materials with a predetermined architecture. Herein, we report the preparation of di- and trivalent silica NPs with polystyrene (PS)/poly(4-vinylbenzyl azide) (PVBA) patches and assemble them in a THF mixture by lowering the solvent quality. Silica-PS/PVBA colloidal hybrid clusters were synthesized through the seeded growth emulsion copolymerization of styrene and 4-vinylbenzyl azide (VBA) in varying ratios.

The protective effect of social support on all-cause and cardio-cerebrovascular mortality among middle-aged and older adults in the US.

The relationship between social support and mortality, especially cardio-cerebrovascular mortality, still has some limitations in the assessment of social support, sample selection bias, and short follow-up time. We used the data from 2005 to 2008 National Health and Nutrition Examination Survey to examine this relationship. The study analyzed a total of 6776 participants, divided into Group 1, Group 2, and Group 3 according to the social support score (0-1; 2-3; 4-5).

Exploring the mechanism of C473D mutation on CDC25B causing weak binding affinity with CDK2/CyclinA by molecular dynamics study.

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved.

Structure-based discovery of a specific SHP2 inhibitor with enhanced blood-brain barrier penetration from PubChem database.

The thiophene [2,3-d]pyrimidine structure-like small molecules were discovered from structure-based virtual screening of 1 billion compounds. Base on enzyme activity assay results, a SHP2-specific molecule inhibitor Comp#2 with IC of 1.174 μM, 85-fold more selective for SHP2 than the highly related SHP1 (IC > 100 μM).

Molecular dynamics study of CDC25B mutant causing the activity decrease of CDC25B.

Cell division cycle 25B (CDC25B) was responsible for regulating the various stages of cell division in the cell cycle. R492L was one of the common types of CDC25B mutants. Researches showed that compared to CDC25B, CDC25B mutant had a ∼100-fold reduction in the rate constant for forming phosphatase intermediate (k).

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

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.

Exploring the dynamic mechanism of allosteric drug SHP099 inhibiting SHP2.

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 SHP2 remains unclear.

Exploring the mechanism of the potent allosteric inhibitor compound2 on SHP2 and SHP2 by molecular dynamics study.

Abnormal activation of Ras/MAPK signaling pathway could trigger excessive cell division. Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2) could promote Ras/MAPK activation by integrating growth factor signals. Thus, SHP2 inhibitors had become a hot topic in the treatment of cancer.

Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and molecular simulation.

PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value.

Design, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors.

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers.

Identification of the potential dual inhibitor of protein tyrosine phosphatase sigma and leukocyte common antigen-related phosphatase by virtual screen, molecular dynamic simulations and post-analysis.

Owing to their inhibitory role in regulating oligodendrocyte differentiation and apoptosis, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR) play a crucial potential role in treating spinal cord injury (SCI) disease. In this research, the computer aided drug design (CADD) methods were applied to discover the potential dual-target drug involving virtual screen, molecular docking and molecular dynamic simulation. Initially, the top 20 compounds with higher docking score than the positive controls (ZINC13749892, ZINC14516161) were virtually screened out from NCI and ZINC databases, and then were submitted in ADMET to predict their drug properties.

Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach.

The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained.

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.

Owing to their unique functions in regulating the synapse activity of protein tyrosine phosphatases delta (PTPδ) that has drawn special attention for developing drugs to autism spectrum disorders (ASDs). In this study, the PTPδ pharmacophore was first established by the structure-based pharmacophore method. Subsequently, 10 compounds contented Lipinski's rule of five was acquired by the virtual screening of the PTPδ pharmacophore against ZINC and PubChem databases.

Identification of potential leukocyte antigen-related protein (PTP-LAR) inhibitors through 3D QSAR pharmacophore-based virtual screening and molecular dynamics simulation.

Owing to its negative regulatory role in insulin signaling, protein tyrosine phosphatase of leukocyte antigen-related protein (PTP-LAR) was widely thought as a potential drug target for diabetes. Now, it was urgent to search for potential LAR inhibitors targeting diabetes. Initially, the pharmacophore models of LAR inhibitors were established with the application of the HypoGen module.

Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation.

SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy.

Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation.

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome (LS), is an autosomal dominant inherited multisystemic disorder. Most patients involve mutation in SHP2 encoded by tyrosine-protein phosphatase non-receptor type 11 (PTPN11) gene. Studies have shown that NSML-associated Y279C mutation exhibited the reduced phosphatase activity, leading to loss-of-function (LOF) of SHP2.

Exploring the effect of inhibitor AKB-9778 on VE-PTP by molecular docking and molecular dynamics simulation.

Diabetic macular edema, also known as diabetic eye disease, is mainly caused by the overexpression of vascular endothelial protein tyrosine phosphatase (VE-PTP) at hypoxia/ischemic. AKB-9778 is a known VE-PTP inhibitor that can effectively interact with the active site of VE-PTP to inhibit the activity of VE-PTP. However, the binding pattern of VE-PTP with AKB-9778 and the dynamic implications of AKB-9778 on VE-PTP system at the molecular level are poorly understood.

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

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.

Exploring the reason for increased activity of SHP2 caused by D61Y mutation through molecular dynamics.

Juvenile myelomonocytic leukaemia, an aggressive myeloproliferative neoplasm, is characterized by thrombocytopenia, splenomegaly, fever and excess myelomonocytic cells. Approximately 35% of patients with JMML occur D61Y mutation in PTPN11, and it increases the activity of the protein. However, the effect of the D61Y mutation on SHP2 conformations in molecular basis is poorly understood.

Exploring the effect of N308D mutation on protein tyrosine phosphatase-2 cause gain-of-function activity by a molecular dynamics study.

One of the most common protein tyrosine phosphatase-2 (SHP2) mutations in Noonan syndrome is the N308D mutation, and it increases the activity of the protein. However, the molecular basis of the activation of N308D mutation on SHP2 conformations is poorly understood. Here, molecular dynamic simulations were performed on SHP2 and SHP2-N308D to explore the effect of N308D mutation on SHP2 cause gain of function activity, respectively.

Exploring the effect of E76K mutation on SHP2 cause gain-of-function activity by a molecular dynamics study.

Juvenile myelomonocytic leukemia (JMML), an invasive myeloproliferative neoplasm, is a childhood disease with very high clinical lethality. Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain-of-function mutation-E76K on SHP2 activity, molecular dynamic simulations on the wild-type SHP2 (SHP2-WT) system and the mutated E76K (SHP2-E76K) system were performed.

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

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.