Design and Synthesis of Small Molecule Probes of MDA-9/Syntenin.

MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this key protein. Genetic algorithm-based computational design and the five-eight step synthesis of three molecules led to ligands with affinities in the range of 1-3 µM, a 20-60-fold improvement over literature reports.

Alteration of Neuropilin-1 and Heparan Sulfate Interaction Impairs Murine B16 Tumor Growth.

Neuropilin-1 acts as a coreceptor with vascular endothelial growth factor receptors to facilitate binding of its ligand, vascular endothelial growth factor. Neuropilin-1 also binds to heparan sulfate, but the functional significance of this interaction has not been established. A combinatorial library screening using heparin oligosaccharides followed by molecular dynamics simulations of a heparin tetradecasaccharide suggested a highly conserved binding site composed of amino acid residues extending across the b1 and b2 domains of murine neuropilin-1.

Computational studies on glycosaminoglycan recognition of sialyl transferases.

Despite decades of research, glycosaminoglycans (GAGs) have not been known to interact with sialyl transferases (STs). Using our in-house combinatorial virtual library screening (CVLS) technology, we studied seven human isoforms, including ST6GAL1, ST6GAL2, ST3GAL1, ST3GAL3, ST3GAL4, ST3GAL5, and ST3GAL6, and predicted that GAGs, especially heparan sulfate (HS), are likely to differentially bind to STs. Exhaustive CVLS and molecular dynamics studies suggested that the common hexasaccharide sequence of HS preferentially recognized ST6GAL1 in a site overlapping the binding site of the donor substrate CMP-Sia.

Supercritical carbon dioxide-decellularized arteries exhibit physiologic-like vessel regeneration following xenotransplantation in rats.

Currently, many techniques are used for decellularization of grafts, including physical, enzymatic, and chemical treatments. Indeed, decellularized xenogenic grafts provide superior outcomes than alternative synthetic conduits. However, vascular grafts produced by these methods are not perfect; their defects include defective vessel wall structures, detergent residues, and the development of aneurysms after grafting.

The alphaherpesvirus conserved pUS10 is important for natural infection and its expression is regulated by the conserved Herpesviridae protein kinase (CHPK).

Conserved Herpesviridae protein kinases (CHPK) are conserved among all members of the Herpesviridae. Herpesviruses lacking CHPK propagate in cell culture at varying degrees, depending on the virus and cell culture system. CHPK is dispensable for Marek's disease herpesvirus (MDV) replication in cell culture and experimental infection in chickens; however, CHPK-particularly its kinase activity-is essential for horizontal transmission in chickens, also known as natural infection.

Glycan Modulation of Insulin-like Growth Factor-1 Receptor.

The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal that activation of IGF-1R by its cognate ligand IGF1 is inhibited by shorter, soluble heparan sulfate (HS) sequences (e.g.

3--Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code.

Heparan sulfate (HS) is arguably the most diverse linear biopolymer that is known to modulate hundreds of proteins. Whereas the configurational and conformational diversity of HS is well established in terms of varying sulfation patterns and iduronic acid (IdoA) puckers, a linear helical topology resembling a cylindrical rod is the only topology thought to be occupied by the biopolymer. We reasoned that 3--sulfation, a rare modification in natural HS, may induce novel topologies that contribute to selective recognition of proteins.

Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states.

Natural glycosaminoglycans (GAGs) are informational molecules with astounding structural diversity. Understanding the behavior of GAGs in the free and protein-bound states is critical for harnessing this diversity. Molecular dynamics (MD) offers atomistic insight into principles governing GAG recognition by proteins.

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism.

GAGs exhibit a high level of conformational and configurational diversity, which remains untapped in terms of the recognition and modulation of proteins. Although GAGs are suggested to bind to more than 800 biologically important proteins, very few therapeutics have been designed or discovered so far. A key challenge is the inability to identify, understand and predict distinct topologies accessed by GAGs, which may help design novel protein-binding GAG sequences.

Aqueous Molecular Dynamics for Understanding Glycosaminoglycan Recognition by Proteins.

Glycosaminoglycans (GAGs) are biopolymers that exist in most organisms. GAGs are known to bind to hundreds of proteins and partake in multiple biological processes such as growth, morphogenesis, inflammation, infection, and others. Their intrinsic structural heterogeneity and conformational variability introduce major challenges in experimental studies.

Combinatorial Virtual Library Screening Study of Transforming Growth Factor-β2-Chondroitin Sulfate System.

Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2-CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations.

Rigorous analysis of free solution glycosaminoglycan dynamics using simple, new tools.

Heparin/heparan sulfates (H/HS) are ubiquitous biopolymers that interact with many proteins to induce a range of biological functions. Unfortunately, how these biopolymers recognize their preferred protein targets remain poorly understood. It is suggested that computational simulations offer attractive avenues but a number of challenges, e.

Perspective on computational simulations of glycosaminoglycans.

Glycosaminoglycans (GAGs) represent a formidable frontier for chemists, biochemists, biologists, medicinal chemists and drug delivery specialists because of massive structural complexity. GAGs are arguably the most complex, natural linear biopolymers with theoretical diversity orders of magnitude higher than proteins and nucleic acids. Yet, this diversity remains generally untapped.

Mucoadhesive role of tamarind xyloglucan on inflammation attenuates ulcerative colitis.

Tamarind xyloglucan (TXG) is edible, bioavailable and mucoadhesive polysaccharide. The aim of this study was (i) to investigate molecular docking studies on the interaction of TXG to MUC1 and cytokine receptors and (ii) to assess the mucoadhesive role of TXG in UC. study: C57Bl6 mice were administered with DSS 3% (w/v) in drinking water; TXG 100 or 300 mg/kg/day was given orally for 7 days simultaneously.

Structural basis, stoichiometry, and thermodynamics of binding of the chemokines KC and MIP2 to the glycosaminoglycan heparin.

Keratinocyte-derived chemokine (KC or mCXCL1) and macrophage inflammatory protein 2 (MIP2 or mCXCL2) play nonredundant roles in trafficking blood neutrophils to sites of infection and injury. The functional responses of KC and MIP2 are intimately coupled to their interactions with glycosaminoglycans (GAGs). GAG interactions orchestrate chemokine concentration gradients and modulate receptor activity, which together regulate neutrophil trafficking.

Magnetic nanoparticles: a versatile carrier for enzymes in bio-processing sectors.

Many industrial processes experience the advantages of enzymes which evolved the demand for enzymatic technologies. The enzyme immobilisation technology using different carriers has trustworthy applications in industrial biotechnology as these techniques encompass varied advantages such as enhanced stability, activity along with reusability. Immobilisation onto nanomaterial is highly favourable as it includes almost all aspects of science.

Analysis of Laser Injection Condition and Electrical Properties in Local BSF for Laser Fired Contact c-Si Solar Cell Applications.

A crystalline silicon (c-Si) local-back-contact (LBC) solar cell for which a laser-condition-optimized surface-recombination velocity (SRV), a contact resistance (Rc), and local back surface fields (LBSFs) were utilized is reported. The effect of the laser condition on the rear-side electrical properties of the laser-fired LBC solar cell was studied. The Nd:YAG-laser (1064-nm wavelength) power and frequency were varied to obtain LBSF values with a lower contact resistance.

So you think computational approaches to understanding glycosaminoglycan-protein interactions are too dry and too rigid? Think again!

Glycosaminoglycans (GAGs) play key roles in virtually all biologic responses through their interaction with proteins. A major challenge in understanding these roles is their massive structural complexity. Computational approaches are extremely useful in navigating this bottleneck and, in some cases, the only avenue to gain comprehensive insight.

Solution structure of CXCL13 and heparan sulfate binding show that GAG binding site and cellular signalling rely on distinct domains.

Chemokines promote directional cell migration through binding to G-protein-coupled receptors, and as such are involved in a large array of developmental, homeostatic and pathological processes. They also interact with heparan sulfate (HS), the functional consequences of which depend on the respective location of the receptor- and the HS-binding sites, a detail that remains elusive for most chemokines. Here, to set up a biochemical framework to investigate how HS can regulate CXCL13 activity, we solved the solution structure of CXCL13.

Reversed-Phase UHPLC Enantiomeric Separation of Rasagiline Salts Using a Chiralpak AGP Column.

We report the first rapid ultra-high performance liquid chromatographic (UHPLC) enantiomeric reversed-phase separation of rasagiline mesylate and its tartrate salts using a Chiralpak AGP column (50 mm × 2.1 mm, 5 μm) as a stationary phase. This method was developed as an alternative to the usage of previously reported normal-phase chiral LC columns for isomer separation.

A molecular dynamics-based algorithm for evaluating the glycosaminoglycan mimicking potential of synthetic, homogenous, sulfated small molecules.

Glycosaminoglycans (GAGs) are key natural biopolymers that exhibit a range of biological functions including growth and differentiation. Despite this multiplicity of function, natural GAG sequences have not yielded drugs because of problems of heterogeneity and synthesis. Recently, several homogenous non-saccharide glycosaminoglycan mimetics (NSGMs) have been reported as agents displaying major therapeutic promise.

Enhanced Haze Ratio on Glass by Novel Vapor Texturing Method.

State-of-the-art optical trapping designs are required to enhance the light trapping capabilities of tandem thin film silicon solar cells. The wet etch process is used to texture the glass surface by dipping in diluted acidic solutions such as HNO3 (nitric acid) and HF (hydrofluoric acid). For vapor texturing, the vapor was generated by adding silicon to HF:HNO3 acidic solution.

Boron Oxygen Pair Effect in p+ Emitter and Nanosized Boron Rich Layer by Fold Coordination Analysis for Crystalline Silicon Solar Cell Applications.

N-type substrates possess better material characteristics than p-type substrates for high efficiency mass producible Si solar cells with HIT, IBC structures. The major drawbacks of these structures are a complicated fabrication process and an expensive unit cost. In this paper, the boron emitter doping profile of a nanosized boron rich layer (BRL), for which the boron and oxygen concentrations are correlated, is optimized to fabricate high efficiency solar cells on an n-type substrate.