Inclusion complexes of β-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study

• Franca Castiglione,
• Fabio Ganazzoli,
• Luciana Malpezzi,
• Andrea Mele,
• Walter Panzeri and
• Giuseppina Raffaini

Beilstein J. Org. Chem. 2017, 13, 714–719, doi:10.3762/bjoc.13.70

• /β-CD and 2/β-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and

• in the solid state from single-crystal X-ray diffraction of 1/β-CD and 2/β-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule

• . Keywords: amitriptyline; β-cyclodextrin; crystal structure; cyclobenzaprine; molecular dynamics simulations; NOE; Introduction The present paper reports on a multidisciplinary approach [1][2] based on single crystal X-ray diffraction, solution NMR spectroscopy and molecular dynamics (MD) simulations with

Conjecture and hypothesis: The importance of reality checks

• David Deamer

Beilstein J. Org. Chem. 2017, 13, 620–624, doi:10.3762/bjoc.13.60

• within a two dimensional plane with the result that polymerization is enhanced [24][25]. The hydrothermal field hypothesis has been tested in laboratory simulations. For instance, peptide bonds have been produced [26][27] and cycles of drying and rehydration have been shown to drive polymerization of

• condition in the above list can be tested by observation, by theoretical analysis or in laboratory simulations. If any one of the predictions fails experimentally or is shown to be impossible, for instance by being inconsistent with thermodynamic principles, that alternative can be considered to be

• falsified. As evidence accumulates, we will be able to judge the relative plausibility and explanatory power of the competing ideas. Continued testing of the alternative hypotheses is essential, because neither has yet reached the level of consensus. In both cases, laboratory simulations will ideally be

Synthesis and optical properties of new 5'-aryl-substituted 2,5-bis(3-decyl-2,2'-bithiophen-5-yl)-1,3,4-oxadiazoles

• Anastasia S. Kostyuchenko,
• Tatyana Yu. Zheleznova,
• Anton J. Stasyuk,
• Aleksandra Kurowska,
• Wojciech Domagala,
• Adam Pron and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2017, 13, 313–322, doi:10.3762/bjoc.13.34

• and aromatic conjugation. Initially, for optical transition simulations, we have used the same functional and basis set as has been used for the ground state geometry optimization, i.e., B3LYP/Def2-SVPD/IEFPCM(DCM). However, the obtained excitation energies revealed an extremely poor agreement between

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

• den Berg et al. [23] and obtained from finite-element simulations [24]. High SNR were obtained at a low-field magnet. Another disadvantage of planar coils is the weak and inhomogenous B1-field produced by the coil resulting in a non-sinusoidal nutation curve and in low SNR of the free induction decay

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• model. The latter is frequently used in expensive computer experiments, and in the case of large-scale process simulations, when evaluations of process models is computationally too expensive. In the case of our test reaction the MBDoE approach enabled us to develop a reasonably good process model in a

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• , agonists, inhibitors, etc. of a target) design. Molecular dynamics (MD) simulations are frequently used in SBDD to give insights into not only how ligands bind with target proteins but also the pathways of interaction and to account for target flexibility. This is especially important when drug targets are

• the Zhang group has also shown great success in recent CASP experiments [57]. QUARK uses atomic knowledge-based potential functions and models are built from small residue fragments by replica exchange Monte Carlo simulations. In both CASP9 and CASP10, QUARK was the number one ranked server in the

• AMBER [120] (Assisted Model Building and Energy Refinement) which have been built mainly for molecular dynamics simulations. The molecular docking program DOCK [121] uses force-field based scoring functions derived from molecular dynamics force-field AMBER. Empirical scoring functions Empirical scoring

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• ]. In the same idea, Mascetti et al. proposed that CDs interact directly with cholesterol [82]. Based on molecular simulations, López et al. proposed the following mechanism: i) association of CDs in aqueous solution to form dimers, ii) binding of dimers at the membrane surface, iii) extraction and

Effects of solvent additive on “s-shaped” curves in solution-processed small molecule solar cells

• John A. Love,
• Shu-Hua Chou,
• Ye Huang,
• Guilllermo C. Bazan and
• Thuc-Quyen Nguyen

Beilstein J. Org. Chem. 2016, 12, 2543–2555, doi:10.3762/bjoc.12.249

• , reduced surface recombination, and interfacial defects leading to traps; device simulations have shown that all of these could indeed result in the s-shape behavior [23][24][25][26][27][28][29][30]. Herein we describe the development of a novel small molecule system with nearly ideal optoelectronic

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• , resulting in the suppression of the β-aggregation propensity. This is in accordance with simulations carried out by Rousseau et al. who proposed that charged amino acid residues flanking aggregating peptide segments could act as gatekeeper residues that reduce the aggregation propensity of the peptide [61

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

• Sean P. Bew,
• Glyn D. Hiatt-Gipson,
• Graham P. Mills and
• Claire E. Reeves

Beilstein J. Org. Chem. 2016, 12, 1081–1095, doi:10.3762/bjoc.12.103

• and high NO concentration. They compared their results with field observations, collected during the Southern oxidant and Aerosol Study (SOAS) campaign conducted in 2013, and model simulations. These studies identified NO as the limiting factor in IPN production [11]. Schwantes et al. reported a

Correction: Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 608–610, doi:10.3762/bjoc.12.59

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• and promising antibacterial agents for the treatment of serious Gram-positive infections. Our predictions rely on force field simulations, supervised by first principle calculations and available experimental data. Different force fields were tested in order to reproduce linezolid's conformational

• ) virtual screenings [28][29][30] of large molecular databases to B) sophisticated simulations of the state equations [31][32]. Nevertheless, both strategies have their own advantages and disadvantages when it comes to the reliable prediction of new drug candidates. While fast virtual screening methods

• flexibility of the U2620 (U2585 in Escherichia coli) moiety has already been discussed elsewhere [20]. Nevertheless, due to our simulation, there is no hydrogen bond between this nucleobase and the morpholine ring. The absence of a second hydrogen bond in our simulations (which is indeed observed for

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• [31][32][33][34]. To acquire evidence for non-statistical dynamic effects, molecular dynamics (MD) simulations are run for a statistically relevant number of trajectories (typically on the order of hundreds or thousands, depending on the system and the starting point for trajectories) [35][36]. The

• questions. MD simulations have been employed to answer two different questions about the chemical reactions discussed below: (1) what mechanism(s) is energetically viable? and (2) do (non-statistical) dynamic effects exert control over product distributions? While trajectories can be started from anywhere

• still not standard practice, but the potential for the utility of dynamics simulations in a variety of systems has certainly been demonstrated. The studies detailed below primarily highlight situations where molecular dynamics simulations were used to quantify “non-IRC” behavior, but the value of

My maize and blue brick road to physical organic chemistry in materials

• Anne J. McNeil

Beilstein J. Org. Chem. 2016, 12, 229–238, doi:10.3762/bjoc.12.24

• simulations with mentorship from my colleague Professor Charles L. Brooks III [36]. Our goal was to model the solid-state interactions as well as the solvent interactions. We wanted to avoid starting the simulation with a crystal structure, knowing that this criterion would ultimately limit the structural

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• capability. However, Monte Carlo simulations by Blake and Jorgensen indicate that the cleft of 9 is actually a good host for chloroform and that the carboxylic acid is solvated by more than one chloroform molecule [21]. Another possibility is that the aromatic cleft might somehow decrease the acidity of the

Aggregation behavior of amphiphilic cyclodextrins in a nonpolar solvent: evidence of large-scale structures by atomistic molecular dynamics simulations and solution studies

• Giuseppina Raffaini,
• Fabio Ganazzoli and
• Antonino Mazzaglia

Beilstein J. Org. Chem. 2016, 12, 73–80, doi:10.3762/bjoc.12.8

• have been usually investigated and characterized in water for their potential use as nanocarriers for drug delivery, but they can also aggregate in apolar solvents, as shown in the present paper through atomistic molecular dynamics simulations and dynamic light scattering measurements. The simulations

• nanoaggregates even in apolar solvents. Keywords: aggregation; amphiphilic cyclodextrins; molecular dynamics; nanoparticles; self-assembly; simulations; Introduction Amphiphilic cyclodextrins (aCD) are a class of molecules highly investigated for their self-assembly properties and inherent potential

• of the initial aggregation stage could easily take place. In particular, these simulations carried out with relatively small systems comprising a few molecules allowed us to assess that the driving force for aggregation was due to a synergy of different contributions. In particular, we found that the

Determination of formation constants and structural characterization of cyclodextrin inclusion complexes with two phenolic isomers: carvacrol and thymol

• Miriana Kfoury,
• David Landy,
• Steven Ruellan,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2016, 12, 29–42, doi:10.3762/bjoc.12.5

• conformations was carried out by a conformational Monte Carlo research method using the MMFFs force field in the presence of water (GB/SA implicit model) with the generation of 5000 conformations (FMNR conjugate gradient minimization convergence fixed to 0.01 kJ Å−1 mol−1). Prior to docking and simulations, the

Physical properties and biological activities of hesperetin and naringenin in complex with methylated β-cyclodextrin

• Waratchada Sangpheak,
• Jintawee Kicuntod,
• Roswitha Schuster,
• Thanyada Rungrotmongkol,
• Peter Wolschann,
• Nawee Kungwan,
• Helmut Viernstein,
• Monika Mueller and
• Piamsook Pongsawasdi

Beilstein J. Org. Chem. 2015, 11, 2763–2773, doi:10.3762/bjoc.11.297

• free energy of inclusion complexes Root mean square displacements (RMSDs) for all atoms of the complex, cyclodextrin and hesperetin in respect with those of initial structures (Figure S1, Supporting Information File 1) suggested that the three independent simulations of β-CD (A1–A3) and DM-β-CD (B1–B3

• Molecular dynamics (MD) simulations with periodic boundary condition were performed on the three best docked structures of the hesperetin/CDs complexes (Figure 7) similar to our previous studies on naringenin/CDs complexes [40][60] using the Amber 12 software package [61]. Note that the docked structures

Aggregation behaviour of amphiphilic cyclodextrins: the nucleation stage by atomistic molecular dynamics simulations

• Giuseppina Raffaini,
• Antonino Mazzaglia and
• Fabio Ganazzoli

Beilstein J. Org. Chem. 2015, 11, 2459–2473, doi:10.3762/bjoc.11.267

• correlating their structures with the pharmaceutical properties. Keywords: aggregation; amphiphilic cyclodextrins; micelles; molecular dynamics simulations; nanoparticles; self-assembly; Introduction Inclusion complexes with supramolecular structures formed by native or modified cyclodextrins (CDs) are

• portion of a whole vesicle [37]. Otherwise, coarse-grained Monte Carlo simulations in two dimensions modelled the self-assembly of aCD [38]. It should be underlined, however, that in the atomistic simulations a manually pre-assembled system was generally assumed, while the spontaneous formation of

• = OH), simply denoted in the following as the model aCD. The simulations used molecular mechanics (MM) and molecular dynamics (MD) methods, and were carried out both in vacuo, to mimic a non-polar and weakly interacting solvent, and in explicit water, using a box of water molecules with periodic

Co-solvation effect on the binding mode of the α-mangostin/β-cyclodextrin inclusion complex

• Chompoonut Rungnim,
• Sarunya Phunpee,
• Manaschai Kunaseth,
• Supawadee Namuangruk,
• Kanin Rungsardthong,
• Thanyada Rungrotmongkol and
• Uracha Ruktanonchai

Beilstein J. Org. Chem. 2015, 11, 2306–2317, doi:10.3762/bjoc.11.251

• anion affinity and selectivity of a neutral anion receptor, bis(cyclopeptide) [17]. Molecular dynamics (MD) simulations can give important insights into the energetics of structural interactions. The hydrated structure of β-CD in aqueous solution [18] and those showing host–guest interactions between

• the β-CD structure and guest molecules in its inclusion compounds have been reported [19][20][21]. Moreover, MD simulations of β-CD in water and ethanol mixtures have been performed to investigate the orientation of the co-solvent in the hydrophobic cavity of the β-CD [22]. Recently, Biedermann et al

• simulations are therefore a useful technique providing details of the molecular interactions of structural components in different environments (e.g., water or water/co-solvent mixtures) which are often encountered in formulations. In our previous work [24], the preliminary results of phase solidities of the

A comprehensive study of olefin metathesis catalyzed by Ru-based catalysts

• Albert Poater and
• Luigi Cavallo

Beilstein J. Org. Chem. 2015, 11, 1767–1780, doi:10.3762/bjoc.11.192

• bond of C2H4 is nearly perpendicular to the Ru–methylidene bond, whereas in the bigger substrate the tether forces the coordinated C=C bond to be almost aligned with the Ru–alkylidene bond. However, the molecular dynamics simulations (vide infra) clearly indicate that in the trans geometries the C2H4

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

• Ana Čikoš,
• Irena Ćaleta,
• Dinko Žiher,
• Mark B. Vine,
• Ivaylo J. Elenkov,
• Marko Dukši,
• Dubravka Gembarovski,
• Marina Ilijaš,
• Snježana Dragojević,
• Ivica Malnar and
• Sulejman Alihodžić

Beilstein J. Org. Chem. 2015, 11, 1447–1457, doi:10.3762/bjoc.11.157

• -dimensional structure and avoid time-consuming molecular dynamic simulations, the starting model of 2 was created from the X-ray single crystal structure of tricyclic spiroketal (CSD entry: ERYTHR) [55], with replacement of the 6-hydroxy group by 6-methoxy. A two-step minimization process consisted of adding

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• results with the devised simulations. More recently, scientists at Novartis (Switzerland) extended this study by developing a semi-continuous flow approach for the synthesis of the oral antidiabetic vildagliptine (77) using in situ generated Vilsmeier reagent (Scheme 13) [74]. Neat streams of DMF and

Cathodic hydrodimerization of nitroolefins

• Michael Weßling and
• Hans J. Schäfer

Beilstein J. Org. Chem. 2015, 11, 1163–1174, doi:10.3762/bjoc.11.131

• experiments they can be clearly assigned to be phenyl protons. Comparable results, as shown for 2, were found for the mixtures of diastereomers of the other hydrodimers. Besides decoupling experiments also 1H NMR simulations give valuable support to assign the complex coupling pattern. This is shown for 18b

Glycoluril–tetrathiafulvalene molecular clips: on the influence of electronic and spatial properties for binding neutral accepting guests

• Yoann Cotelle,
• Marie Hardouin-Lerouge,
• Stéphanie Legoupy,
• Olivier Alévêque,
• Eric Levillain and
• Piétrick Hudhomme

Beilstein J. Org. Chem. 2015, 11, 1023–1036, doi:10.3762/bjoc.11.115

• . The stepwise oxidation of each molecular clip involves an electrochemical mechanism with three one-electron processes and two charge-coupled chemical reactions, a scheme which is supported by electrochemical simulations. The fine-tunable π-donating ability of the TTF units and the cavity size allow to

• measurements demonstrated that the mixed-valence state in these fused glycoluril-TTF molecular clips seems to originate from intermolecular TTF interactions, according to measurements at various concentrations and to cyclic voltammogram simulations. Spatial and electrochemical properties were shown to be

• . (middle) 3D representation: x-axis = wavelength, y-axis = time and z-axis = absorbance. (bottom) concentration-time profiles of each simulated species in the thin layer (50 µm) calculated from electrochemical simulations of Figure 4 (E1 = 0.090 V, E2 = 0.165 V, E3 = 0.435 mV, KMV = 11400 M−1, KDIM = 680 M