| 1. |
- Bergström, Per, et al.
(author)
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Scaling Behaviour of Strength of 3D-, Semi-flexible-, Cross-linked Fibre Network
- 2019
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In: International Journal of Solids and Structures. - : Elsevier BV. - 0020-7683 .- 1879-2146. ; 166:July 2019, s. 68-74
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Journal article (peer-reviewed)abstract
- Anisotropic, semi-flexible, cross-linked, random fibre networks are ubiquitous both in nature and in a wide variety of industrial materials. Modelling mechanical properties of such networks have been done extensively in terms of criticality, mechanical stability, and scaling of network stiffnesses with structural parameters, such as density. However, strength of the network has received much less attention. In this work we have constructed 3D-planar fibre networks where fibres are, more or less, oriented in the in-plane direction, and we have investigated the scaling of network strength with density. Instead of modelling fibres as 1D element (e.g., a beam element with stretching, bending and/or shear stiffnesses), we have treated fibres as a 3D-entity by considering the features like twisting stiffness, transverse stiffness, and finite cross-link (or bond) strength in different deformation modes. We have reconfirmed the previous results of elastic modulus in the literature that, with increasing density, the network modulus indeed undergoes a transition from bending-dominated deformation to stretching-dominated with continuously varying scaling exponent. Network strength, on the other hand, scales with density with a constant exponent, i.e., showing no obvious transition phenomena. Using material parameters for wood fibres, we have found that the predicted results for stiffness and strength agree very well with experimental data of fibre networks of varying densities reported in the literature.
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| 2. |
- Hjalte, Johanna, et al.
(author)
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Aggregation Behavior of Structurally Similar Therapeutic Peptides Investigated by 1H NMR and All-Atom Molecular Dynamics Simulations
- 2022
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In: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:3, s. 904-917
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Journal article (peer-reviewed)abstract
- Understanding of peptide aggregation propensity is an important aspect in pharmaceutical development of peptide drugs. In this work, methodologies based on all-atom molecular dynamics (AA-MD) simulations and 1H NMR (in neat H2O) were evaluated as tools for identification and investigation of peptide aggregation. A series of structurally similar, pharmaceutically relevant peptides with known differences in aggregation behavior (D-Phe6-GnRH, ozarelix, cetrorelix, and degarelix) were investigated. The 1H NMR methodology was used to systematically investigate variations in aggregation with peptide concentration and time. Results show that 1H NMR can be used to detect the presence of coexisting classes of aggregates and the inclusion or exclusion of counterions in peptide aggregates. Interestingly, results suggest that the acetate counterions are included in aggregates of ozarelix and cetrorelix but not in aggregates of degarelix. The peptides investigated in AA-MD simulations (D-Phe6-GnRH, ozarelix, and cetrorelix) showed the same rank order of aggregation propensity as in the NMR experiments. The AA-MD simulations also provided molecular-level insights into aggregation dynamics, aggregation pathways, and the influence of different structural elements on peptide aggregation propensity and intermolecular interactions within the aggregates. Taken together, the findings from this study illustrate that 1H NMR and AA-MD simulations can be useful, complementary tools in early evaluation of aggregation propensity and formulation development for peptide drugs.
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| 3. |
- Hossain, Md Shakhawath, et al.
(author)
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Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation
- 2019
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In: AAPS PharmSciTech. - : SPRINGER. - 1530-9932. ; 20
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Journal article (peer-reviewed)abstract
- Medium chain fatty acids (MCFA) are digestion products of lipid-rich food and lipid-based formulations, and they are used as transient permeability enhancers in formulation of poorly permeable compounds. These molecules may promote drug absorption by several different processes, including solubilization, increased membrane fluidity, and increased paracellular transport through opening of the tight junctions. Therefore, understanding the aggregation behavior of MCFAs is important. A number of studies have measured the critical micelle concentration (CMC) of MCFAs experimentally. However, CMC is highly dependent on system conditions like pH, temperature, and the ionic strength of the buffer used in different experimental techniques. In this study, we investigated the aggregation behavior of four different MCFAs using the coarse-grained molecular dynamics (CG-MD) simulations with the purpose to explore if CG-MD can be used to study MCFA interactions occurring in water. The ratio of deprotonated and non-charged MCFA molecules were manipulated to assess aggregation behavior under different pH conditions and within the box sizes of 22x22x44nm(3) and 44nm(3) for 1s. CMCs were calculated by performing CG-MD simulations with an increasing number of MCFAs. The resulting aggregate size distribution and number of free MCFA molecules were used to determine the CMC. The CMCs from simulations for C-8, C-10, and C-12 were 1.8-3.5-fold lower than the respective CMCs determined experimentally by the Wilhelmy method. However, the variation of MCFA aggregate sizes and morphologies at different pH conditions is consistent with previous experimental observation. Overall, this study suggests that CG-MD is suitable for studying colloidal systems including various MCFAs.
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| 4. |
- Hossain, Md Shakhawath, et al.
(author)
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Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers
- 2022
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In: Processes. - : MDPI. - 2227-9717. ; 10:1, s. 29-
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Journal article (peer-reviewed)abstract
- Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or the opening of the tight junctions. To elucidate these mechanistic details, it is important to understand the aggregation behavior of not only the PEs themselves but also other molecules already present in the intestine. Aggregation processes depend critically on, among other factors, the charge state of ionizable chemical groups, which is affected by the pH of the system. In this study, we used explicit-pH coarse-grained molecular dynamics simulations to investigate the aggregation behavior and pH dependence of two commonly used PEs—caprate and SNAC—together with other components of fasted- and fed-state simulated intestinal fluids. We also present and validate a coarse-grained molecular topology for the bile salt taurocholate suitable for the Martini3 force-field. Our results indicate an increase in the number of free molecules as a function of the system pH and for each combination of FaSSIF/FeSSIF and PEs. In addition, there are differences between caprate and SNAC, which are rationalized based on their different molecular structures and critical micelle concentrations.
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| 5. |
- Hossain, Md Shakhawath, et al.
(author)
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Molecular simulation as a computational pharmaceutics tool to predict drug solubility, solubilization processes and partitioning
- 2019
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In: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 137, s. 46-55
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Research review (peer-reviewed)abstract
- In this review we will discuss how computational methods, and in particular classical molecular dynamics simulations, can be used to calculate solubility of pharmaceutically relevant molecules and systems. To the extent possible, we focus on the non-technical details of these calculations, and try to show also the added value of a more thorough and detailed understanding of the solubilization process obtained by using computational simulations. Although the main focus is on classical molecular dynamics simulations, we also provide the reader with some insights into other computational techniques, such as the COSMO-method, and also discuss Flory-Huggins theory and solubility parameters. We hope that this review will serve as a valuable starting point for any pharmaceutical researcher, who has not yet fully explored the possibilities offered by computational approaches to solubility calculations.
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| 6. |
- Hossain, Md Shakhawath, et al.
(author)
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Revealing the interaction between peptide drugs and permeation enhancers in the presence of intestinal bile salts
- 2023
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In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 15:47, s. 19180-19195
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Journal article (peer-reviewed)abstract
- Permeability enhancer-based formulations offer a promising approach to enhance the oral bioavailability of peptides. We used all-atom molecular dynamics simulations to investigate the interaction between two permeability enhancers (sodium caprate, and SNAC), and four different peptides (octreotide, hexarelin, degarelix, and insulin), in the presence of taurocholate, an intestinal bile salt. The permeability enhancers exhibited distinct effects on peptide release based on their properties, promoting hydrophobic peptide release while inhibiting water-soluble peptide release. Lowering peptide concentrations in the simulations reduced peptide-peptide interactions but increased their interactions with the enhancers and taurocholates. Introducing peptides randomly with enhancer and taurocholate molecules yielded dynamic molecular aggregation, and reduced peptide-peptide interactions and hydrogen bond formation compared to peptide-only systems. The simulations provided insights into molecular-level interactions, highlighting the specific contacts between peptide residues responsible for aggregation, and the interactions between peptide residues and permeability enhancers/taurocholates that are crucial within the mixed colloids. Therefore, our results can provide insights into how modifications of these critical contacts can be made to alter drug release profiles from peptide-only or mixed peptide-PE-taurocholate aggregates. To further probe the molecular nature of permeability enhancers and peptide interactions, we also analyzed insulin secondary structures using Fourier transform infrared spectroscopy. The presence of SNAC led to an increase in beta-sheet formation in insulin. In contrast, both in the absence and presence of caprate, alpha-helices, and random structures dominated. These molecular-level insights can guide the design of improved permeability enhancer-based dosage forms, allowing for precise control of peptide release profiles near the intended absorption site. Molecular-level insights can guide the design of improved permeability enhancer-based dosage forms, allowing for precise control of peptide release profiles near the intended absorption site.
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| 9. |
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| 10. |
- Hossain, Shakhawath, et al.
(author)
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Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers
- 2020
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In: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8392 .- 1543-8384. ; 17:11, s. 4226-4240
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Journal article (peer-reviewed)abstract
- Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.
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