19 research outputs found
Integration of advanced methods and models to study drug absorption and related processes : An UNGAP perspective
Funding Information: AI acknowledges the support of projects icp009 (ALKOOL) of PRACE-ICEI (grant agreement 800858) for awarding access to Piz Daint, at the Swiss National Supercomputing Centre (CSCS), Switzerland and BG05M2OP001–1.001–0004 (UNITe) of the Bulgarian Ministry of Education and Science. For further details on points raised in this article, please contact [email protected]. Funding Information: Acknowledgements. JAGH is supported by the Biocenter Finland, the Helsinki Institute of Life Sciences, and the Faculty of Pharmacy, University of Helsinki. Publisher Copyright: © 2021 The AuthorsThis collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.Peer reviewe
Solvent Reorganization Energies in A-DNA, B-DNA, and Rhodamine 6G−DNA Complexes from Molecular Dynamics Simulations with a Polarizable Force Field
Systematic Study of the Influence of Base-Step Parameters on the Electronic Coupling between Base-Pair Dimers: Comparison of A-DNA and B-DNA Forms
Structure and Undulations of Escin Adsorption Layer at Water Surface Studied by Molecular Dynamics
The saponin escin, extracted from horse chestnut seeds, forms adsorption layers with high viscoelasticity and low gas permeability. Upon deformation, escin adsorption layers often feature surface wrinkles with characteristic wavelength. In previous studies, we investigated the origin of this behavior and found that the substantial surface elasticity of escin layers may be related to a specific combination of short-, medium-, and long-range attractive forces, leading to tight molecular packing in the layers. In the current study, we performed atomistic molecular dynamics simulations of 441 escin molecules in a dense adsorption layer with an area per molecule of 0.49 nm2. We found that the surfactant molecules are less submerged in water and adopt a more upright position when compared to the characteristics determined in our previous simulations with much smaller molecular models. The number of neighbouring molecules and their local orientation, however, remain similar in the different-size models. To maintain their preferred mutual orientation, the escin molecules segregate into well-ordered domains and spontaneously form wrinkled layers. The same specific interactions (H-bonds, dipole–dipole attraction, and intermediate strong attraction) define the complex internal structure and the undulations of the layers. The analysis of the layer properties reveals a characteristic wrinkle wavelength related to the surface lateral dimensions, in qualitative agreement with the phenomenological description of thin elastic sheets
Self-Assembly of Escin Molecules at the Air−Water Interface as Studied by Molecular Dynamics
This is the final peer-reviewed manuscript accepted for publication in Langmuir.
Citation of the published version is: Langmuir 33, 8330-8341 (2017
Structure and Undulations of Escin Adsorption Layer at Water Surface Studied by Molecular Dynamics
The saponin escin, extracted from horse chestnut seeds, forms adsorption layers with high viscoelasticity and low gas permeability. Upon deformation, escin adsorption layers often feature surface wrinkles with characteristic wavelength. In previous studies, we investigated the origin of this behavior and found that the substantial surface elasticity of escin layers may be related to a specific combination of short-, medium-, and long-range attractive forces, leading to tight molecular packing in the layers. In the current study, we performed atomistic molecular dynamics simulations of 441 escin molecules in a dense adsorption layer with an area per molecule of 0.49 nm2. We found that the surfactant molecules are less submerged in water and adopt a more upright position when compared to the characteristics determined in our previous simulations with much smaller molecular models. The number of neighbouring molecules and their local orientation, however, remain similar in the different-size models. To maintain their preferred mutual orientation, the escin molecules segregate into well-ordered domains and spontaneously form wrinkled layers. The same specific interactions (H-bonds, dipole–dipole attraction, and intermediate strong attraction) define the complex internal structure and the undulations of the layers. The analysis of the layer properties reveals a characteristic wrinkle wavelength related to the surface lateral dimensions, in qualitative agreement with the phenomenological description of thin elastic sheets
Density Functional Theory Assessment of the Environment Polarity Effect on Polyaniline–Water Coupling
Crystallization
water plays an important role in the self-organization
of oligomer chains in conducting polyaniline. In order to quantify
the interaction between emeraldine salt and such a water, models containing
a tetramer in bipolaronic or polaronic form, chloride counterions,
and an explicit water molecule are used. Different initial positions
of water with respect to the oligomer chainî—¸tangential and
verticalî—¸are considered. Various media are simulated by introducing
an implicit solvent continuum of decreasing polarity. The DFT-D3/PCM
computational approach is employed to examine the behavior of the
systems in several aspectsî—¸the role of the explicit water position
and the effect of the environment polarity on the spatial structure,
energetics, charge distribution, and the frontier molecular orbital
energies. The strength of hydrogen bonding and the patterns of charge
redistribution invoked by the water molecule are discussed. The study
establishes trend lines in the variation of the molecular characteristics
upon change of milieu as a tool for control of the self-assembly process.
The results show that chains interact more efficiently with tangentially
placed water. The influence of the environment polarity is minor and
is mainly expressed in slight shortening of the intermolecular distances
and mild decrease of the group charges of the system components with
reduction of polarity
P1001: MODULATION OF MUTANT CALRETICULIN-DRIVEN ONCOGENESIS IN MYELOPROLIFERATIVE NEOPLASMS BY CLASSICAL HLA GENES
Magnetostructural Correlation for Rational Design of Mn(II) Hybrid-Spin Complexes
The magnetic properties of a series of manganeseÂ(II)
diacetylacetonate
and dihexafluoroacetylacetonate hybrid-spin complexes with neutral
pyridine-based organic radicals were characterized theoretically by
DFT calculations. Three stable radicals, in which a radical group
is bound in either para or meta position with respect to the pyridine
nitrogen atom, were considered. The correct stable structures and
multiplets of the complexes were obtained by full geometry optimization
starting from an ideal structure. A total of three important geometry
descriptors of the complexes were monitored and related to their magnetic
characteristics. These structural parameters are (i) the torsion angle
governing the conjugation of the organic radical <b><i>m</i>-PyNO</b> (anti versus gauche), (ii) the coordination geometry
of the acetyl acetonate ligands around the metal ion (square versus
rhombic), and (iii) the relative orientation of the organic radical
with respect to the acetyl acetonate plane (parallel versus perpendicular).
It was found that the magnetic properties are not sensitive to the
orientation of the radicals with respect to the equatorial plane but
do depend on the conformation of the organic radicals. Even a spin
switch between the ferromagnetic (<i>S</i> = <sup>7</sup>/<sub>2</sub>) and antiferromagnetic (<i>S</i> = <sup>3</sup>/<sub>2</sub>) ground state was found to be feasible for one of the
complexes upon variation of the organic radical geometry, namely,
the dihedral angle between the organic radical moiety and the pyridine
ring. The pattern of molecular orbital overlap was determined to be
the key factor governing the exchange coupling in the modeled systems.
Bonding π-type overlap provides antiferromagnetic coupling in
all complexes of the para radicals. In the meta analogues, the spins
are coupled through the σ orbitals. A low-spin ground state
occurs whenever a continuous σ-overlap pathway is present in
the complex. Ferromagnetic interaction requires σ–π
orthogonality of the pyridine atomic orbitals and/or π-antibonding
Mn–pyridine natural orbital overlap. Using an estimate of the
donor–acceptor energy stabilization, the affinity of a given
MnÂ(II) d-orbital to mix with the sp<sup>2</sup> orbital from pyridine
can be predicted
Novel Cerium(IV) Coordination Compounds of Monensin and Salinomycin
The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M4+ and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce4+. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL2(OH)2] and [CeL(NO3)2(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO3)2(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin