1,721,145 research outputs found
Xanthan gum in drug delivery
No full textThis chapter explores the versatile uses of xanthan gum (XG) in the formulation of drug delivery systems (DDSs). XG, a natural polysaccharide derived from Xanthomonas campestris, has received significant attention from the pharmaceutical industry because of its unique rheological properties, biocompatibility, and mucoadhesive nature. The contribution provides an overview of this biopolymer, its structure, properties, and various formulations used in drug delivery. It discusses the role of XG in the development of sustained-release formulations, targeted DDSs, mucoadhesive drug carriers, and nanoparticulate systems. In addition, the chapter highlights recent advances, challenges, and future perspectives in utilizing XG to improve drug delivery efficiency and therapeutic outcomes. © 2025 Elsevier Ltd. All rights reserved
A new frontier for modeFRONTIER: an orchestrator for molecular simulation symphony
No full textThe successful application of high throughput molecular simulations to determine biochemical properties would be of great importance to the biomedical community if such simulations could be turned around in a clinically relevant timescale. An important example is the determination of inhibitor efficacy against varying tyrosine kinase proteins in cancer target therapy through calculation of drug-protein binding affinities.
Here, we describe the Binding Affinity Calculator (BAC), i.e., a modeFRONTIER-integrated molecular simulation tool for the automated calculation of protein-ligand binding affinities (Figure 1). The tool employs fully atomistic molecular simulations alongside the well-established Molecular Mechanics Poisson-Boltzmann Solvent Accessible Surface Area (MMPBSA) free energy methodology to enable the calculation of the binding free energy of several ligand-protein complexes, including several mutant kinase proteins known to be both the etiological agents of different cancer types and the eventual cause of ultimate drug resistance and pathological resurgence.
This enables the efficacy of these inhibitors to be ranked towards the original aberrant protein as well as across several mutant clinical isolates.
BAC is a tool that utilizes the power provided by modeFRONTIER to automate all of the stages required to compute free energies of binding: model preparation, equilibration, simulation, post-processing, and data-marshaling, fully exploiting all compute resources utilized. Such automation enables the molecular dynamics methodology to be used in a high throughput manner not achievable by manual methods. This paper describes the architecture and workflow management of BAC and the function of each of its components. Given adequate compute resources, BAC can yield quantitative information regarding drug activity and resistance at the molecular level in a timescale of direct clinical relevance, and can assist in decision support for the assessment of patient-specific optimal drug treatment and the subsequent response to therapy for any given genotype
MoDeNa Nanotools: An integrated multiscale simulation workflow to predict thermophysical properties of thermoplastic polyurethanes
No full textIn this work we describe and assess the performance of Nanotools, a feature of the MoDena software we arecurrently developing in the framework of a granted EU project devoted to the implementation of a multi-scale modeling environment for nanomaterials and systems by design. Specifically, Nanotools integratesmulti-step computational procedures based on atomistic molecular dynamics and Monte Carlo simula-tions for the estimation of major thermophysical properties of thermoplastic polyurethanes (TPUs). Thepredicted results obtained with Nanotools for density, thermal conductivity, surface tension, gas perme-ability, and Young modulus are in good agreement with the relevant experimental data, thus paving theway for the use of Nanotools in the current design of new TPUs for advanced applications
In silico design of self-assembly nanostructured polymer systems by multiscale molecular modeling
Full text linkThe fast development of digitalization and computational science is opening new possibilities
for a rapid design of new materials. Computational tools coupled with focused experiments can
be successfully used for the design of new nanostructured materials in different sectors, particularly
in the area of biomedical applications. This paper starts with a general introduction on
the future of computational tools for the design of new materials and introduces the paradigm
of multiscale molecular modeling. It then continues with the description of the multiscale (i.e.,
atomistic, mesoscale and finite element calculations) computational recipe for the prediction of
novel materials and structures for biomedical applications. Finally, the comparison of in silico
and experimental results on selected systems of interest in the area of life sciences is reported
and discussed. The quality of the agreement obtained between virtual and real data for such
complex systems indeed confirms the validity of computational tools for the design of nanostructured
polymer systems for biomedical applications
Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study
Full text link: Drug binding to human serum albumin (HSA) significantly affects in vivo drug transport and biological activity. To gain insight into the binding mechanism of the two B-Raf tyrosine kinase inhibitors dabrafenib and vemurafenib to HSA, in this work, we adopted a combined strategy based on fluorescence spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and molecular simulations. Both anticancer drugs are found to bind spontaneously and with a 1:1 stoichiometry within the same binding pocket, located in Sudlow's site II (subdomain IIIA) of the protein with comparable affinity and without substantially perturbing the protein secondary structure. However, the nature of each drug-protein interactions is distinct: whereas the formation of the dabrafenib/HSA complex is more entropically driven, the formation of the alternative vemurafenib/HSA assembly is prevalently enthalpic in nature. Kinetic analysis also indicates that the association rate is similar for the two drugs, whereas the residence time of vemurafenib within the HSA binding pocket is somewhat higher than that determined for the alternative B-Raf inhibitor
Molecular Interactions of Cobimetinib and Vemurafenib with Human Serum Albumin: a Comparative Biophysical and Computational Analysis
No full textThe combined use of BRAF and MEK inhibitors has transformed the management of BRAFV600-mutated melanoma, yet the pharmacokinetic interplay between cobimetinib (COB) and vemurafenib (VEM) remains incompletely understood. Here, we investigated the binding interactions of COB and VEM with human serum albumin (HSA) using a multidisciplinary approach combining fluorescence spectroscopy, isothermal titration calorimetry, circular dichroism, and molecular simulations. Both inhibitors form stable complexes with HSA, predominantly at Sudlow’s site II, driven by different interactions pattern. Thermodynamic and kinetic analyses revealed distinct binding behaviors: COB binding is entropy-driven (ΔH = +5.88 ± 0.32 kJ/mol; ΔG = −24.19 kJ/mol), with a dissociation constant (Kd) of 58.2 μM and a residence time of 1.45 s, indicating rapid and dynamic engagement. In contrast, VEM displays a more enthalpy-favored profile (ΔH = −22.05 ± 0.31 kJ/mol), stronger binding affinity (Kd≈ 4.8 μM), and a longer residence time of 18.5 s. Stoichiometry for both ligands is approximately 1:1, as determined by ITC. Structural analyses revealed subtle conformational alterations in HSA upon ligand binding, while enzymatic assays demonstrated that both COB and VEM competitively inhibit HSA’s esterase-like activity. These findings highlight distinct binding kinetics and functional consequences for each drug, offering critical insights into their pharmacokinetic behavior during combination therapy and providing a foundation for optimizing systemic exposure and therapeutic efficacy
Complexes between poly(amido amine) dendrimers and poly(methacrlyic acid): insight from molecular dynamics simulations
No full textIn this work we present results from fully atomistic molecular dynamics simulations of aqueous solutions of poly(amido amine) dendrimers and poly(methacrylic) acid in the dilute regime and at low ionic strength and physiological pH conditions, in which the polymeric components are charged. We have studied stoichiometric (1:1) and non-stoichiometric (1:2) systems, comprised by dendrimers of two different generations and two different lengths of the linear polyelectrolyte. For all systems studied, a polymer-rich and a solvent-rich region is formed. The polymer-rich region consists of aggregated complexes between the polymeric components bearing similarities to percolated structures met in physical hydrogels. We examine morphological characteristics of the two components as well as the degree of ionic pairing between the different ionic moieties, providing information regarding the degree of physical adsorption of the linear chains on the dendrimer’s surface and that of the respective counterions on the oppositely charged monomers
Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair
Full text linkGENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY ΔGBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTIO
Structure and binding thermodynamics of viologen-phosphorous dendrimers to human serum albumin: A combined computational/experimental investigation
No full textLow-generation viologen-phosphorous dendrimers (VPDs) can be exploited as novel therapeutic agents, since they efficiently inhibit aggregation of amyloid-β into fibrils and are active against several strains of microorganisms. Human serum albumin (HSA), the most abundant plasma protein, is playing an increasing role as drug carrier in the clinical setting. Therefore, with the aim of exploiting HSA as a potential carrier for VPDs, in this work we performed a preliminary investigation of the interaction of six different VPDs 1–6 with HSA using a combined computational/experimental approach. First, different modeling techniques were employed to i) determine the dendrimer binding site on the HSA surface; ii) derive the free energy change ΔGb involved in each dendrimer/HSA complex formation; iii) analyze in details all molecular determinants contributing to ΔGb, and iv) evaluate the eventual HSA structural variations induced by dendrimer binding. All modeling predictions were next validated using a series of experimental techniques, including isothermal titration calorimetry (ITC), circular dichroism (CD), and fluorescence quenching and decay. In aggregate, the results from this study allowed us to rank the affinity of the different viologen-phosphorous dendrimers 1–6 towards HSA and to formulate a molecular-based rationale for the differential binding thermodynamics of the resulting dendrimer/HSA complexes. According to our data, HSA can successfully and selectively bind VPDs 1–6, dendrimer 4 being the best cargo for this endogenous protein nanocarrier
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