130 research outputs found
Progettazione,sintesi ed affinitĂ recettoriali di nuovi ligandi sigma
2008/2009Questo lavoro di tesi presenta un progetto riguardante il design, la sintesi e l'affinitĂ recettoriale di nuovi ligandi dei recettori sigma. I recettori sigma sono coinvolti nella modulazione e nella biosintesi di vari neurotrasmettitori, nella regolazione di alcuni comportamenti umani e nella regolazione della vita cellulare. In particolare in questo lavoro viene presentata la creazione di un modello farmacoforico per i recettori sigma1 ed il suo successivo utilizzo come strumento predittivo per la progettazione e la sintesi di nuove molecole dotate di affinitĂ sigma-recettoriale.XXII Ciclo198
Mixed-monolayer functionalized gold nanoparticles for cancer treatment: Atomistic molecular dynamics simulations study.
Gold nanoparticles (AuNPs) are employed as drug carriers due to their inertness, non-toxicity, and ease of synthesis. An experimental search for the optimal AuNP design would require a systematic variation of physico-chemical properties which is time-consuming and expensive. Computational methods provide quicker and cheaper approach to complement experiments and provide useful guidelines. In this paper, we performed atomistic molecular dynamics simulations to study how the size, hydrophobicity, and concentration of the drug affect the structure of functionalized AuNPs in the aqueous environment. We simulated two groups of nano-systems functionalized with a zwitterionic background ligand, and a ligand carrying a drug (Quinolinol or Panobinostat). Results indicate that in the case of a hydrophobic drug (Quinolinol), the hydrophobicity drives the conformation changes of the coating layer. The tendency of the hydrophobic drug to reduce its solvent-accessible surface results in a decrease of the coating thickness and the overall NP size. Although the amount of accessible drug can be increased by increasing its initial concentration, it will compromise the solubility of the system. In the case of a hydrophilic drug (Panobinostat), the ligand in excess has a dominant influence on the final structure of the coating conformations. The percentage of accessible drug is significantly higher than in the hydrophobic systems for any given ratio. It implies that for hydrophilic systems we can generally expect higher biological efficiency. Our results highlight the importance of taking into account physico-chemical properties of drugs and ligands when developing gold-based nanosystems, especially in the case of hydrophobic drugs
Perceptions and Misconceptions in Molecular Recognition: Key Factors in Self-Assembling Multivalent (SAMul) Ligands/Polyanions Selectivity
Biology is dominated by polyanions (cell membranes, nucleic acids, and polysaccharides just to name a few), and achieving selective recognition between biological polyanions and synthetic systems currently constitutes a major challenge in many biomedical applications, nanovectors-assisted gene delivery being a prime example. This review work summarizes some of our recent efforts in this field; in particular, by using a combined experimental/computation approach, we investigated in detail some critical aspects in self-assembled nanomicelles and two major polyanions-DNA and heparin
Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled In Silico-Experimental Studies. Part I: Covalent siRNA Nanocarriers
Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the clinical translation of RNA interference (RNAi) requires safe and efficient vectors for siRNA delivery into cells. Dendrimers are attractive nanovectors to serve this purpose, as they present a unique, well-defined architecture and exhibit cooperative and multivalent effects at the nanoscale. This short review presents a brief introduction to RNAi-based therapeutics, the advantages offered by dendrimers as siRNA nanocarriers, and the remarkable results we achieved with bio-inspired, structurally flexible covalent dendrimers. In the companion paper, we next report our recent efforts in designing, characterizing and testing a series of self-assembled amphiphilic dendrimers and their related structural alterations to achieve unprecedented efficient siRNA delivery both in vitro and in vivo
Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled in Silico-Experimental Studies. Part II: Self-Assembled siRNA Nanocarriers
In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing
Thermoplastic Materials for the Metal Replacement of Non-Structural Components in Marine Engines
Metal replacements for automotive and aerospace components are already a consolidated reality, in light of the advantages offered by fibre-reinforced polymers, consisting of reduced costs, weight, and environmental impact. As a result, engineering has been studying the possibility of replacing currently used metallic alloys with alternative materials, such as thermoplastic fibre-reinforced polymers, in the manufacturing of non-structural sections of marine engines. Given the peculiar characteristics of the working environment of such parts, i.e., ship engine spaces, and the strict requirements regarding safety, the selection of the polymer must be properly performed through a tailored material design process. Consequently, the redesign of the components must be carried out with the aim of exploiting the best of the materials’ properties while ensuring the correct resistance and simplifying installation operations. In this framework, finite element simulations may represent a suitable approach to validate the conformity of the proposed material and design. In this paper, this methodology is applied to a camshaft cover of a four-stroke marine engine, currently made of aluminium alloy. A 30% wt GFs/PA6,6 was identified as the most promising material and the novel plastic cover proved to guarantee the correct resistance while ensuring an important reduction in weight, processing costs, and required energy
Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics
In this paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of
triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modelling of the interactions
between tubulin and the title compounds allows to propose a molecular rationale for their biological activity
Improving selectivity preserving affinity: New piperidine-4-carboxamide derivatives as effective sigma-1-ligands
We report the design, synthesis and binding evaluation against \u3c31 and \u3c32 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on \u3c3 receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward \u3c31 and \u3c32 receptors. Very high \u3c31 affinity (Ki\ua0=\ua03.7\ua0nM) and Ki\u3c32/Ki\u3c31 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom
Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays-structure-activity effects on DNA/heparin binding
This paper reports that modifying the ligands in self-assembled multivalent (SAMul) displays has an impact on apparent binding selectivity towards two nanoscale biological polyanions-heparin and DNA. For the nanostructures assayed here, spermidine ligands are optimal for heparin binding but spermine ligands are preferred for DNA. Probing subtle differences in such nanoscale binding interfaces is a significant challenge, and as such, several experimental binding assays-competition assays and isothermal calorimetry-are employed to confirm differences in affinity and provide thermodynamic insights. Given the dynamic nature and hierarchical binding processes involved in SAMul systems, we employed multiscale modelling to propose reasons for the origins of polyanion selectivity differences. The modelling results, when expressed in thermodynamic terms and compared with the experimental data, suggest that DNA is a shape-persistent polyanion, and selectivity originates only from ligand preferences, whereas heparin is more flexible and adaptive, and as such, actively reinforces ligand preferences. As such, this study suggests that inherent differences between polyanions may underpin subtle binding selectivity differences, and that even simple electrostatic interfaces such as these can have a degree of tunability, which has implications for biological control and regulation on the nanoscale
Emergence of highly-ordered hierarchical nanoscale aggregates on electrostatic binding of self-assembled multivalent (SAMul) cationic micelles with polyanionic heparin
We report three surfactants, with cationic N,N-di-(3-aminopropyl)-N-methylamine (DAPMA) head groups and aliphatic chains connected via an amide linkage, and investigate their ability to self-assemble and bind polyanionic heparin – a process of potential clinical importance in coagulation control. Modifying the hydrophobic chain length tunes the self-assembly event, with C16-DAPMA having the lowest critical micelle concentration and also being the optimal heparin binder. Remarkably highly structured hierarchical nanoscale aggregates are formed on binding between the spherical cationic micelles and linear polyanionic heparin. C14-DAPMA and C16-DAPMA yield organized polycrystalline assemblies as observed by transmission electron microscopy (TEM), predicted in solution by mesoscale simulations and characterized by small-angle X-ray scattering (SAXS). This confirms that the micelles remain intact during the hierarchical assembly process and become packed in a face-centered cubic manner. The nanoscale assembly formed by C16-DAPMA showed the highest degree of order. Importantly, these studies indicate the impact of hydrophobic modification on self-assembly and heparin binding, demonstrate remarkably high stability of these self-assembled micelles even when forming strong electrostatic interactions with heparin, and provide structural insights into nanoscale hierarchical electrostatic assemblies
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