Remdesivir interactions with sulphobutylether-β-cyclodextrins: a case study using selected substitution patterns

Modified cyclodextrins (CDs) consist of a distribution of different structures with different number and location of the substituted groups. Among the most important applications of these molecules is their use as an enabling excipient in pharmaceutical formulations to provide the necessary solubility, stability and bioavailability for a drug to be effectively used. The most typical interaction mechanism of small molecular groups with CDs is the formation of host–guest inclusion complexes. The thermodynamic affinity constant between CDs and drugs should not be too strong, since then the biological activity could be negated by the formation of the complex. In the opposite scenario, if the affinity constant is too weak, the complex is barely formed and the amount of CD required in the formulation may become too great. Thus, a balance between the affinity of the CD and the drug is necessary for an optimal formulation. Additionally in the case of modified CDs and specific drug complexes there are further questions concerning the effect that the locations and number of substitutions plays in complexation. In the present work, this question is explored by using sulphobutylether-β-cyclodextrin and remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, as a case study. This paper presents results from an orthogonal study using isothermal titration calorimetry measurements and biased molecular dynamics simulations that provide complementary information. Isothermal titration calorimetry delves into the global impact of the species distribution while molecular dynamics simulations deals with specific chemical structures. The goal is to provide useful information to optimize pharmaceutical formulations based on modified CDs, specifically in the case of remdesivir, used to treat SARS-CoV-2 infection, although the main conclusions could be extended to the interaction of other drugs with modified cyclodextrinsR.G.-F thanks to the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00) and for a “Ramón y Cajal” contract (RYC-2016-20335), to Xunta de Galicia (ED431F 2020/05) and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund - ERDF). Á. P. thanks to the Ministerio de Ciencia e Innovación (PID2019-111327GB-I00). We thank the “Centro de Supercómputo de Galicia” (CESGA) for computing time as well as for their exceptional technical supportS

Aggregation versus inclusion complexes to solubilize drugs with cyclodextrins. A case study using sulphobutylether-β-cyclodextrins and remdesivir

The formation of small hybrid aggregates between excipient and drug molecules is one of the mechanisms that contributes to the solubilization of active principles in pharmaceutical formulations. The characterization of the formation, governing interactions and structure of such entities is not trivial since they are highly flexible and dynamic, quickly exchanging molecules from one to another. In the case of cyclodextrins, this mechanism and the formation of inclusion complexes synergistically cooperate to favour the bioavailability of drugs. In a previous study we reported a detailed characterization of the possible formation of inclusion complexes with 1:1 stoichiometry between remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, and sulphobutylether-β-cyclodextrins. Here we extend our study to assess the role of the spontaneous aggregation in the solubilization of the same drug, by molecular dynamics simulations at different relative concentrations of both compounds. The number of sulphobutylether substitutions in the cyclodextrin structure and two different protonation states of the remdesivir molecule are considered. We aim to shed light in the solubilization mechanism of sulphobutylether-β-cyclodextrins, broadly used as an excipient in many pharmaceutical formulations, in particular in the case of remdesivir as an active compoundR.G.-F thanks to the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00) and for a “Ramón y Cajal” contract (RYC-2016-20335), to Xunta de Galicia (ED431F 2020/05) and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund - ERDF). Á. P. thanks to the Ministerio de Ciencia e Innovación (PID2019-111327 GB-I00)S

Rings, Hexagons, Petals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes

The basket-like geometry of cyclodextrins (CDs), with a cavity able to host hydrophobic groups, makes these molecules well suited for a large number of fundamental and industrial applications. Most of the established CD-based applications rely on trial and error studies, often ignoring key information at the atomic level that could be employed to design new products and to optimize their use. Computational simulations are well suited to fill this gap, especially in the case of CD systems due to their low number of degrees of freedom compared with typical macromolecular systems. Thus, the design and validation of solid and efficient methods to simulate and analyze CD-based systems is key to contribute to this field. The behavior of supramolecular complexes critically depends on the media where they are embedded, so the detailed characterization of the solvent is required to fully understand these systems. In the present work, we use the inclusion complex formed by two α-CDs and one sodium dodecyl sulfate molecule to test eight different parameterizations of the GROMOS and AMBER force fields, including several methods aimed to increase the conformational sampling in computational molecular dynamics simulation trajectories. The system proved to be extremely sensitive to the employed force field, as well as to the presence of a water/air interface. In agreement with previous experiments and in contrast to the results obtained with AMBER, the analysis of the simulations using GROMOS showed a quick adsorption of the complex to the interface as well as an extremely exotic behavior of the water molecules surrounding the structure both in the bulk aqueous solution and at the water surface. The chirality of the CD molecule seems to play an important role in this behavior. All together, these results are expected to be useful to better understand the behavior of CD-based supramolecular complexes such as adsorption or aggregation driving forces, as well as to introduce new methods able to speed up general MD simulationsThis work was supported by the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00), and by the Xunta de Galicia and the ERDF (ED431C 2017/25 and Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09). P.F.G. is funded by a predoctoral research grant (BES-2016-076761) from the Spanish Ministry of Economy and Competitiveness and the European Social Fund. M.C. is funded by a predoctoral fellowship from Xunta de Galicia. R.G.-F. is a “Ramón y Cajal” fellowship (RYC-2016-20335) from the Ministerio de Ciencia, Innovación y UniversidadesS

Effects of applied pressure in ZnV2 O4 and evidences for a dimerized structure

The series of V spinels [A2+] V2 O4 (A = Cd, Mn, Zn, Mg) provides an opportunity to tune the V-V distance continuously, in the frustrated pyrochlore lattice of the spinel. This system has been shown to approach the metallic state when V-V distance is reduced. The proximity to the transition leads to a dimerized structure in ZnV2 O4 caused by lattice instabilities. A different manner to tune the V − V distance of this structure is to fix the A2+ cation (in our case, Zn) and apply pressure. We have analyzed the evolution of the electronic structure of the system in the dimerized state. Such structure prevents the system to present a metallic phase at moderate pressures. We have also calculated the transport properties in a semiclassical approach based on Boltzmann transport theory. Our results support the validity of this structural distortion by providing a nice fit with experimental measurementsThe authors thank the CESGA (Centro de Supercomputacion de Galicia) for the computing facilities and the Ministerio de Educación y Ciencia (MEC) for the financial support through the project MAT2009-08165. A.S.B. thanks MEC for an FPU grant. J.B. and M.P. acknowledge Deputación da Coruña and the Isabel Barreto program respectively for financial support. We are also thankful to the Xunta de Galicia for financial support through the project INCITE08PXIB236052PRS

Electronic structure analysis of the quasi-one-dimensional oxide Sr6Co5O15 within the LDA+U method

The quasi-one-dimensional cobalt oxide Sr6Co5O15 is studied using first-principles electronic-structure calculations and Boltzmann transport theory. We have been able to describe the electronic structure, characterized by the structural one-dimensionality and a particular type of charge ordering, with unexpected electronic structure of the different Co atoms. The origin of the large unquenched misaligned orbital angular momenta comes out naturally from a correct description of the different crystal-field environments. The evolution with the on-site Coulomb repulsion (U) of the electronic structure and the transport properties is discussed, with a best agreement with experiment found for the smallest value of U that allows to converge the correct in-chain ferrimagnetic ground stateThe authors thank the CESGA for the computing facilities, the Ministerio de Educación y Ciencia (MEC) for the financial support through the project MAT2009-08165, the Ministerio de Ciencia e Innovación (MICINN) for the project MAT2007-60536 and the Xunta de Galicia for the project INCITE08PXIB236052PR. A.S.B. thanks MEC for a FPU grant. M.P. and J.B. thank Isabel Barreto program and Deputación da Coruña, respectively, for financial supportS

Not so rigid capsids based on cyclodextrin complexes: keys to design

Membranes based on cyclodextrin complexes can be used as functional nanocarrier envelopers by chemical modifications of the cyclodextrin hydroxyl groups or by encapsulating different ligands in their cavities. Experiments: Molecular dynamics simulations of monolayers and bilayers based on supramolecular complexes consisting of two α or β-cyclodextrin and one sodium dodecylsulfate or dodecane at 283 K and at 298 K were performed. Findings: It is shown that the structure and main interactions stabilizing the membranes, as well as their permeability to water and ions can be tuned by changing the cyclodextrin, the ligand, the number of layers or/and the temperature. These results provide new evidences about both their dynamic nature and the interactions responsible for the stabilization of the membranes and will facilitate the design of new functional capsides and applications based on cyclodextrin complexesThis work has received financial support from the Spanish Agencia Estatal de Investigación (AEI) and the European Regional Development Fund - ERDF (PID2019-111126RB-100, RTI2018-098795-A-I00, and PID2019-111327GB-I00) and by the Xunta de Galicia (ED431F 2020/05 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (ERDF). R.G.-F. thanks Ministerio de Ciencia, Innovación y Universidades for a “Ramón y Cajal” contract (RYC-2016-20335). P. F. G. thanks the Spanish Ministry of Economy and Competitiveness and the European Social Fund for his predoctoral research grant, reference BES-2016-076761.S

Simple approximation for aggregation number determination by isothermal titration calorimetry: STAND-ITC

A new proposal to obtain aggregation numbers from isothermal titration calorimetry dilution experiments is described and tested using dodecyl trimethyl ammonium bromide, dodecyl methylimidazolium chloride, dodecyl methylimidazolium sulfonate, and didecyl methylimidazolium chloride aqueous solutions at different temperatures. The results were compared to those obtained from fluorescence measurements and also with data from the literature. In addition to the aggregation number, the molar free energy to transfer a solute molecule from the aggregate to the bulk solution, the enthalpy corresponding to the formation of the self-assembled suprastructures, the molar heat corresponding to the dilution of monomers and aggregates, and an offset parameter to account for unpredictable external contributions are simultaneously obtained using the same method. The new equations are compared to those obtained from previous proposals, and they are also analyzed in detail to assess the impact of each fitting parameter in the profile of the calorimetric isotherm. This new approach has been implemented in a computational code that automatically determines the fitting parameters as well as the corresponding statistical uncertainties for the large variety of calorimetric profiles that have been tested. Given the high sensitivity of the dilution experiments to the aggregation number for relatively small assemblies, our approach is proposed also to quantify the oligomerization state of biomolecules such as proteins and peptidesThe authors thank the financial support of the Spanish Ministry of Economy and Competitiveness and the Agencia Estatal de Investigación (AEI) (projects MAT2015-71826-P, CTQ2017-84254-P, and PID2019-111327GB-I00 to Á.P.), Xunta de Galicia (GR 2007/085 and IN607C 2016/03), and Centro Singular de Investigación de Galicia accreditation 2016-2019 (ED431G/09). P.F.G. thanks the Spanish Ministry of Economy and Competitiveness and the European Social Fund for his predoctoral research grant, reference BES-2016-076761. These research projects were partially supported by European ERDF Funds (MCIU/AEI/FEDER, EU)S

Uncovering the mechanisms of cyclic peptide self-assembly in membranes with the chirality-aware MA(R/S)TINI forcefield

Cyclic peptides (CPs) formed by alternation of D- and L-amino acids (D,L-CPs) can self-assemble into nanotubes (SCPNs) by parallel or/and antiparallel stacking. Different applications have been attributed to these nanotubes, including the disruption of lipid bilayers of specific compositions and the selective transport of ions throughout membranes. Molecular dynamics (MD) simulations have significantly contributed to understand the interaction between CPs, including the structural, dynamic and transport properties of their supramolecular aggregates. The high computational cost of atomic resolution forcefields makes them impractical for simulating the self-assembly of macromolecules, so coarse-grained (CG) models might represent a more feasible solution for this purpose. However, general CG models used for the simulation of biomolecules such as the MARTINI forcefield do not explicitly consider the non-covalent interactions leading to the formation of secondary structure patterns in proteins. This becomes particularly important in the case of CPs due to the D- and L-chirality alternation in their sequence, leading to opposite orientations of the backbone polar groups on both sides of the cyclic ring plane. In order to overcome this limitation, we have extended the MARTINI forcefield to introduce chirality in each residue of the CPs. The new parametrization, which we have called MA(R/S)TINI, reproduces the expected self-assembly patterns for several CP sequences in the presence of different membrane models, explicitly considering the chirality of the CPs and with no significant extra computational cost. Our simulations provide new mechanistic information of how these systems self-assemble in presence of different lipid scenarios, showing that the CP-CP and CP-membrane interactions are sensitive to the peptide sequence chirality. This opens the door to design new bioactive CPs based on CG-MD simulations. A web-based tool for the automatic parameterization of new CP sequences using MA(R/S)TINI, among other functionalities, is under construction (see http://cyclopep.com)This work was supported by the Spanish Agencia Estatal de Investigación (AEI) (RTI2018-098795-A-I00, PID2019-111327GB-I00, PID2019-111126RB-100 and PDC2022-133402-I00), by Xunta de Galicia (ED431F 2020/05, ED431B 2022/36, ED431C 2017/25 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund - ERDF). R.G.-F. thanks Ministerio de Ciencia, Innovación y Universidades for a “Ramón y Cajal” contract (RYC-2016-20335)S