Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling molecular dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a parallel artificial membrane permeability assay (PAMPA). The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic collaboration with numerous in vitro PAMPA permeability assays. The presented computational model introduces itself as a useful, predictive tool for permeability prediction.
Individuals with borderline personality disorder (BPD) often experience deficits in social role functioning, which encompasses the ability to adhere to socially defined rules and norms of behaviour. Additionally, research suggests that coping styles influence the way individuals with BPD manage stress and that symptom presentation and functioning in individuals with BPD vary across genders. This study sought to explore these variables via moderated mediation, investigating the mediating influence of coping styles on the association between BPD symptoms and social role dysfunction and if these associations were further moderated by gender. Participants (N = 233) were outpatients attending a programme for personality dysfunction. Participants completed measures of BPD symptoms, coping styles and social role dysfunction. Moderated mediation indicated that for women, emotion-oriented coping and social diversion-oriented coping mediated the association between BPD symptoms and social dysfunction. While BPD symptoms were positively associated with emotion coping, which was positively associated with social role dysfunction, BPD symptoms were negatively associated with social diversion coping, which was negatively associated with social role dysfunction. For men, coping did not mediate the association between BPD symptoms and social role dysfunction. Our findings may indicate that social support and a healthy social network may play an important part in the ongoing social role functioning of women with BPD. From this, potential early therapeutic interventions targeting safe social engagement in times of stress may decrease the pervasive and persistent nature of social dysfunction in BPD.
The role of ribonucleic acid (RNA) in molecular biology is shifting from a mere messenger between DNA and proteins to an important player in many cellular activities. The central role of RNA molecules calls for a precise characterization of their structural and dynamical properties. Nowadays, experiments can be efficiently complemented by computational approaches. Within this framework, elastic network models (ENMs) are valuable and efficient tools for characterizing the collective internal dynamics of biomolecules starting from the sole knowledge of their structures. The increasing evidence that the biological functionality of RNAs is often linked to their innate internal motions, poses the question of whether ENM approaches can be successfully extended to these biomolecules. This issue, which is still largely unexplored, is tackled here by considering various families of elastic networks for a representative set of RNAs. The large-scale motions predicted by the alternative ENMs are stringently validated by comparison against extensive molecular dynamics (MD) simulations and SHAPE experimental data. We propose a specific combination of three ENM centroids (sugarbase-phosphate) as an optimal compromise capable of reproducing simulations and experiments. Membrane permeability is a key property to consider in drug design, especially when the drugs in question need to cross the blood-brain barrier (BBB). A comprehensive in vivo assessment of the BBB permeability of a drug takes considerable time and financial resources. A current, simplified in vitro model to investigate drug permeability is a Parallel Artificial Membrane Permeability Assay (PAMPA) that generally provides higher throughput and initial quantification of a drug's passive permeability. Computational methods can also be used to predict drug permeability. These methods are highly advantageous as they do not require the synthesis of the desired drug, and can be implemented rapidly using high-performance computing. In this study, we have used umbrella sampling Molecular Dynamics (MD) methods to assess the passive permeability of a range of compounds through a lipid bilayer. Furthermore, the permeability of these compounds was comprehensively quantified using the PAMPA assay to calibrate and validate the MD methodology. After demonstrating a firm correlation between the two approaches, we then implemented our MD method to quantitatively predict the most permeable potential drug from a series of potential scaffolds. This permeability was then confirmed by the in vitro PAMPA methodology. Thus, in this work we have illustrated the potential that these computational methods hold as useful tools to help predict a drug's permeability in a faster and more cost-effective manner. Release number: LLNL-ABS-677757. . Recently, Harko and Mak considered two mathematical reaction-diffusion models of gioblastoma growth (Mathematical Biosciences and Engineering 12 41-69 (2015)). They obtained exact travelling wave solutions for particular functional choices of the diffusion...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.