| 1. |
- Hjalte, Johanna, et al.
(författare)
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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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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:3, s. 904-917
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Hossain, Md Shakhawath, et al.
(författare)
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Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation
- 2019
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Ingår i: AAPS PharmSciTech. - : SPRINGER. - 1530-9932. ; 20
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Hossain, Md Shakhawath, et al.
(författare)
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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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Ingår i: Processes. - : MDPI. - 2227-9717. ; 10:1, s. 29-
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Hossain, Md Shakhawath, et al.
(författare)
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Molecular simulation as a computational pharmaceutics tool to predict drug solubility, solubilization processes and partitioning
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 137, s. 46-55
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Forskningsöversikt (refereegranskat)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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| 5. |
- Hossain, Md Shakhawath, et al.
(författare)
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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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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 15:47, s. 19180-19195
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Tidskriftsartikel (refereegranskat)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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| 6. |
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| 7. |
- Kabedev, Aleksei, et al.
(författare)
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Molecular Dynamics Simulations as a Tool to Understand Drug Solubilization in Pharmaceutical Systems
- 2023
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Ingår i: Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. - : Elsevier.
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Bokkapitel (refereegranskat)abstract
- This chapter aims to explore the use of molecular dynamics (MD) simulations to investigate the solubilization of drugs by various surfactants and excipients. Examples from the literature are presented to demonstrate that MD simulations provide valuable insights into the solubilization mechanisms, and several metrics for predicting drug solubility in complex formulations are also presented and discussed. We also indicate the potential that is to be found in this area by the combination of MD simulations with machine learning methods.
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| 8. |
- Kneiszl, Rosita C., et al.
(författare)
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In Silico-Based Experiments on Mechanistic Interactions between Several Intestinal Permeation Enhancers with a Lipid Bilayer Model
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:1, s. 124-137
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Tidskriftsartikel (refereegranskat)abstract
- Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNAC─all with a negative charge─and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70–100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.
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| 9. |
- Liu, Kang-Cheng, et al.
(författare)
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Membrane insertion mechanism of the caveola coat protein Cavin1
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:25
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades, and lipid sorting. The caveola coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking. Here, we used model membranes combined with biophysical dissection and computational modeling to show that Cavin1 inserts into membranes. We establish that initial phosphatidylinositol (4, 5) bisphosphate [PI(4,5)P2]-dependent membrane adsorption of the trimeric helical region 1 (HR1) of Cavin1 mediates the subsequent partial separation and membrane insertion of the individual helices. Insertion kinetics of HR1 is further enhanced by the presence of flanking negatively charged disordered regions, which was found important for the coassembly of Cavin1 with Caveolin1 in living cells. We propose that this intricate mechanism potentiates membrane curvature generation and facilitates dynamic rounds of assembly and disassembly of Cavin1 at the membrane.
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| 10. |
- Naranjani, Benyamin, et al.
(författare)
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Numerical simulation of peristalsis to study co-localization and intestinal distribution of a macromolecular drug and permeation enhancer
- 2023
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Ingår i: International Journal of Biological Macromolecules. - : Elsevier. - 0141-8130 .- 1879-0003. ; 240
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Tidskriftsartikel (refereegranskat)abstract
- In this work, simulations of intestinal peristalsis are performed to investigate the intraluminal transport of macromolecules (MMs) and permeation enhancers (PEs). Properties of insulin and sodium caprate (C10) are used to represent the general class of MM and PE molecules. Nuclear magnetic resonance spectroscopy was used to obtain the diffusivity of C10, and coarse-grain molecular dynamics simulations were carried out to estimate the concentration-dependent diffusivity of C10. A segment of the small intestine with the length of 29.75 cm was modeled. Peristaltic speed, pocket size, release location, and occlusion ratio of the peristaltic wave were varied to study the effect on drug transport. It was observed that the maximum concentration at the epithelial surface for the PE and the MM increased by 397 % and 380 %, respectively, when the peristaltic wave speed was decreased from 1.5 to 0.5 cm s−1. At this wave speed, physiologically relevant concentrations of PE were found at the epithelial surface. However, when the occlusion ratio is increased from 0.3 to 0.7, the concentration approaches zero. These results suggest that a slower-moving and more contracted peristaltic wave leads to higher efficiency in transporting mass to the epithelial wall during the peristalsis phases of the migrating motor complex.
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| 11. |
- Salo-Ahen, Outi M. H., et al.
(författare)
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Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
- 2021
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Ingår i: Processes. - : MDPI. - 2227-9717. ; 9:1
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Forskningsöversikt (refereegranskat)abstract
- Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.
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