Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

Predicting short-term weight loss using four leading health behavior change theories

<p>Abstract</p> <p>Background</p> <p>This study was conceived to analyze how exercise and weight management psychosocial variables, derived from several health behavior change theories, predict weight change in a short-term intervention. The theories under analysis were the Social Cognitive Theory, the Transtheoretical Model, the Theory of Planned Behavior, and Self-Determination Theory.</p> <p>Methods</p> <p>Subjects were 142 overweight and obese women (BMI = 30.2 ± 3.7 kg/m²; age = 38.3 ± 5.8y), participating in a 16-week University-based weight control program. Body weight and a comprehensive psychometric battery were assessed at baseline and at program's end.</p> <p>Results</p> <p>Weight decreased significantly (-3.6 ± 3.4%, p < .001) but with great individual variability. Both exercise and weight management psychosocial variables improved during the intervention, with exercise-related variables showing the greatest effect sizes. Weight change was significantly predicted by each of the models under analysis, particularly those including self-efficacy. Bivariate and multivariate analyses results showed that change in variables related to weight management had a stronger predictive power than exercise-specific predictors and that change in weight management self-efficacy was the strongest individual correlate (p < .05). Among exercise predictors, with the exception of self-efficacy, importance/effort and intrinsic motivation towards exercise were the stronger predictors of weight reduction (p < .05).</p> <p>Conclusion</p> <p>The present models were able to predict 20–30% of variance in short-term weight loss and changes in weight management self-efficacy accounted for a large share of the predictive power. As expected from previous studies, exercise variables were only moderately associated with short-term outcomes; they are expected to play a larger explanatory role in longer-term results.</p

Who will lose weight? A reexamination of predictors of weight loss in women

BACKGROUND: The purpose of this study was to analyze pretreatment predictors of short-term weight loss in Portuguese overweight and obese women involved in a weight management program. Behavioral and psychosocial predictors were selected a priori from previous results reported in American women who participated in a similar program. METHODS: Subjects were 140 healthy overweight/obese women (age, 38.3 ± 5.9 y; BMI, 30.3 ± 3.7 kg/m(2)) who participated in a 4-month lifestyle weight loss program consisting of group-based behavior therapy to improve diet and increase physical activity. At baseline, all women completed a comprehensive behavioral and psychosocial battery, in standardized conditions. RESULTS: Of all starting participants, 3.5% (5 subjects) did not finish the program. By treatment's end, more than half of all women had met the recomended weight loss goals, despite a large variability in individual results (range for weight loss = 19 kg). In bivariate and multivariate correlation/regression analysis fewer previous diets and weight outcome evaluations, and to a lesser extent self-motivation and body image were significant and independent predictors of weight reduction, before and after adjustment for baseline weight. A negative and slightly curvilinear relationship best described the association between outcome evaluations and weight change, revealing that persons with very accepting evaluations (that would accept or be happy with minimal weight change) lost the least amount of weight while positive but moderate evaluations of outcomes (i.e., neither low nor extremely demanding) were more predictive of success. Among those subjects who reported having initiated more than 3–4 diets in the year before the study, very few were found to be in the most successful group after treatment. Quality of life, self-esteem, and exercise variables did not predict outcomes. CONCLUSIONS: Several variables were confirmed as predictors of success in short-term weight loss and can be used in future hypothesis-testing studies and as a part of more evolved prediction models. Previous dieting, and pretreatment self-motivation and body image are associated with subsequent weight loss, in agreement with earlier findings in previous samples. Weight outcome evaluations appear to display a more complex relationship with treatment results and culture-specific factors may be useful in explaining this pattern of association

Rational design of novel fluorescent tagged glutamic acid dendrimers with different terminal groups and in-silico analysis of their properties

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behaviour and structure activity relationships has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer aided molecular design and molecular dynamics simulations to identify optimal topology of a Poly(L-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole, NBD and oregon-488, ORG) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behaviour. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD PG G4 can provide a suitable scaffold to be used for biophysical studies of surface modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system.Peer reviewedFinal Published versio

Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E

Botulinum Neurotoxins (BoNT) are the most potent toxins currently known. However, they also have therapeutic applications for an increasing number of motor related conditions due to their specificity, and low diffusion into the system. Although the start- and end- points for the BoNT mechanism of action are well-studied, a critical step remains poorly understood. It is theorised that BoNTs undergo a pH-triggered conformational shift, activating the neurotoxin by priming it to form a transmembrane (TM) channel. To test this hypothesis, we combined molecular dynamic (MD) simulations and small-angle x-ray scattering (SAXS), revealing a new conformation of BoNT/E. This conformation was exclusively observed in simulations below pH 5.5, as determined by principal component analysis (PCA), and its theoretical SAXS profile matched an experimental SAXS profile obtained at pH 4. Additionally, a localised secondary structural change was observed in MD simulations below pH 5.5, in a region previously identified as instrumental for membrane insertion for BoNT/A. These changes were found at a critical pH value for BoNTs in vivo, and may be relevant for their therapeutic use

Reciprocal effects among changes in weight, body image, and other psychological factors during behavioral obesity treatment: a mediation analysis

<p>Abstract</p> <p>Background</p> <p>Changes in body image and subjective well-being variables (e.g. self-esteem) are often reported as outcomes of obesity treatment. However, they may, in turn, also influence behavioral adherence and success in weight loss. The present study examined associations among obesity treatment-related variables, i.e., change in weight, quality of life, body image, and subjective well-being, exploring their role as both mediators and outcomes, during a behavioral obesity treatment.</p> <p>Methods</p> <p>Participants (BMI = 31.1 ± 4.1 kg/m²; age = 38.4 ± 6.7 y) were 144 women who attended a 12-month obesity treatment program and a comparison group (n = 49), who received a general health education program. The intervention included regular group meetings promoting lasting behavior changes in physical activity and dietary intake. Body image, quality of life, subjective well-being, and body weight were measured at baseline and treatment's end. Mediation was tested by multiple regression and a resampling approach to measure indirect effects. Treatment group assignment was the independent variable while changes in weight and in psychosocial variables were analyzed alternatively as mediators and as dependent variables.</p> <p>Results</p> <p>At 12 months, the intervention group had greater weight loss (-5.6 ± 6.8% vs. -1.2 ± 4.6%, p < .001) and larger decreases in body size dissatisfaction (effect size of 1.08 vs. .41, p < .001) than the comparison group. Significant improvements were observed in both groups for all other psychosocial variables (effect sizes ranging from .31–.75, p < .05). Mediation analysis showed that changes in body image and body weight were concurrently mediators and outcomes of treatment, suggesting reciprocal influences. Weight loss partially mediated the effect of treatment on quality of life and on self-esteem but the reciprocal effect was not observed.</p> <p>Conclusion</p> <p>Changes in weight and body image may reciprocally affect each other during the course of behavioral obesity treatment. No evidence of reciprocal relationships was found for the other models under analysis; however, weight changes partially explained the effects of treatment on quality of life and self-esteem. Weight and psychosocial changes co-occur during treatment and will probably influence each other dynamically, in ways not yet adequately understood. Results from this study support the inclusion of intervention contents aimed at improving body image in weight management programs.</p

Innovation for resilience

Last decade is characterized by different types of crises and shocs in the socioeconomic systems, creating a turbulent context and calling for a better understanding of what the dynamic perspective of change is. For countries, regions and cities a better understanding of governance urges and calls for action

Partially glycosylated dendrimers block MD-2 and prevent TLR4-MD-2-LPS complex mediated cytokine responses.

The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4'phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases