A spectroscopic and molecular modeling studies of the inclusion complexes of orciprenaline and terbutaline drugs with native and modified cyclodextrins

The inclusion complexation behavior of orciprenaline (ORC) and terbutaline (TER) with α-CD, β-CD, HP-α-CD and HP-β-CD are examined by absorption, fluorescence, life time and molecular modeling methods. ORC and TER forms 1:1 (CD/drug) inclusion complexes in lower CD concentrations and 1:2 (CD/drug) inclusion complexes with higher CD concentrations. The inclusion of both drugs with HP-CDs was stronger than that of native CDs. Both drugs exhibit dual emission (excimer) in the CD solution, whereas in water single emission is seen. The hydrogen bonding and van der Waals interaction between the drugs and the CD plays an important role in the inclusion complexes. Computational results show the side chain of the drugs encapsulated in the CD cavity. The molecular modeling results by PM3 were in good agreement with the experimental results.     

Cobalt(II) complexes of biologically active glutathione: spectroscopic and molecular modeling studies

Cobalt(II) complexes of reduced glutathione (GSH) of general composition Na[Co(L)(X)].nH2O (where H2L = GSH; X = Cl-, NO3-, NCS-, CH3CO2-, HCO2-, ClO4- and n = 0-4) have been synthesized and characterised by elemental analyses, vibrational spectra, electronic spectra, magnetic susceptibility measurements, thermal studies and molecular modeling studies. Electronic spectra indicate planar geometry for all the complexes. Infrared spectra indicate the presence of H2O molecules (except perchlorate complex) in the complexes that has been supported by TG/DTA. The room temperature magnetic moment values for all complexes lie in the range of 2.60-2.80 BM range indicating departure from spin only values due to second order Zeeman effect. Thermal decomposition of all the complexes proceeds via first order kinetics. The Na[Co(L)(Cl)].2H2O complex has the minimum activation energy and Na[Co(L)(CH3CO2)].3H2O has the maximum activation energy. The molecular modeling calculation for energy minimization optimizes geometry of the metal complexes.     

Volume and heat capacity studies to evidence interactions between cyclodextrins and nicotinic acid in water

Density and heat capacity of the water+cyclodextrin (CD), water+nicotinic acid (NA) and water+CD+NA mixtures were determined at 298.15 K. CDs with different cavity size and alkylation were selected. From the experimental data the apparent molar properties were calculated. Assuming the formation of inclusion complexes of 1:1 stoichiometry, these properties were modeled and provided the stability constants of CD/NA inclusion complexes and the corresponding property change. The binding of NA with the smallest sized α-cyclodextrin (α-CD) generates more stable complexes accompanied by the lower volume and the heat capacity changes. These results are in agreement with earlier proposed binding mode according to which deep insertion of NA into α-CD takes place and it is governed by the hydrophobic-hydrophilic forces. The volume and the heat capacity changes caused by the interactions of CDs with NA were interpreted in terms of cosphere overlap model and the release of water molecules from the CD cavity due to the NA incorporation.     

Studies on the interaction mechanism between CXS and papain by spectroscopic and molecular modeling methods

We have studied the interaction between cefuroxime sodium (CXS) and papain at different temperatures by a fluorescence method, and confirmed that the mechanism of fluorescence quenching of CXS to papain is mainly static quenching. We also determined the binding constant K. Based on the thermodynamic functions at different temperatures, the results show that the major forces between CXS and papain are van der Waals’ forces and H bond. According to the Forster non-radiation energy transfer mechanism, we determined the binding distance between CXS and papain, and studied the confirmation effect of CXS to papain by synchronous fluorescence and UV–Vis spectroscopy. Molecular simulations show that the binding types of CXS and papain are van der Waals’ forces, hydrophobic interaction, and H-bond.     

Understanding the Hofmeister effect in interactions between chaotropic anions and lipid bilayers: molecular dynamics simulations

A set of all-atom molecular dynamics simulations have been performed to better understand critical phenomena regarding a Hofmeister series of anions and lipid bilayers. The simulations isolate the effect of anion size and show clear differences in the interactions with the dipolar phoshpatidylcholine headgroup. Cl- anions penetrate into the headgroup region of the bilayer, but the simulations confirm theories which predict that larger anions penetrate more deeply, into a more heterogeneous and hydrophobic molecular region. That anion size leads to such differences in partitioning in the bilayer provides atomic-level support to hypotheses inspired by several experimental studies. The ability of larger anions to bury deep within the bilayer is correlated with a less well-structured hydration shell, shedding of which upon penetration incurs a smaller penalty for the larger anions than for Cl-.     

Interfacial interactions between amphiphilic cyclodextrins and physiologically relevant cations

The compression isotherms of a series of amphiphilic cyclodextrins, formed (a) by acylation at the secondary hydroxyl face and (b) by acylation accompanied by varying degrees of sulfatation (DS) at the primary hydroxyl face (DS=0, 4, and 7), have been studied on subphases of pure water and of water containing NaCl, KCl, MgCl(2), and CaCl(2) at inter- and extracellular concentrations. The formation of solid lipid nanoparticles (SLNs) by two of the molecules has been observed, while these do not aggregate at concentrations of monovalent salts up to 150 mM for the sulfated derivative. In the presence of divalent salts one of these with a DS=0 for sulfatation degree flocculates at divalent salt concentrations below 0.1 mM while the other with a DS=4 flocculates at Mg(2+) concentration above 5 mM and a Ca(2+) concentration above 3 mM. AFM noncontact mode imaging has been carried out, in air, for the SLNs deposited on mica.     

Study of the complexation of resveratrol with cyclodextrins by spectroscopy and molecular modeling

In present work the complexation of Res with two kinds of cyclodextrins (CDs), native β-cyclodextrin (β-CD) and modified hydroxypropyl-β-cyclodextrin (HP-CD), have been investigated by fluorescence spectroscopy, ¹H-NMR spectroscopy and molecular modeling methods. The stoichiometric ratios, inclusion constants and thermodynamic parameters have been determined by the fluorescence data. In all cases 1:1 inclusion complexes are formed. The inclusion ability of HP-CD is larger than that of β-CD. Both inclusion processes have negative ?G, negative ?H and positive ?S. Thermodynamic analysis suggests that Van der Waals force of guest-host interactions and the release of high-enthalpy water molecules from the cavity of CDs play important roles in driving complex formation. The study of molecular modeling shows that part of the A-ring and the B-ring of Res are placed in the cavity of β-CD, and the hydroxyl groups are projected outside. As for Res in HP-CD, the B-ring of Res is included in the cavity of HP-CD, and part of the A-ring is pointed outside. ¹H-NMR spectroscopy results show that H_2, H₃, H₄ and H₅ protons of Res are more affected by the complexatin, indicating that they are located inside the torus of CDs, which are in agreement with the result of the molecular modeling.     

Carbohydrate molecular recognition: a spectroscopic investigation of carbohydrate-aromatic interactions

The physical basis of carbohydrate molecular recognition at aromatic protein binding sites is explored by creating molecular complexes between a series of selected monosaccharides and toluene (as a truncated model for phenylalanine). They are formed at low temperatures under molecular beam conditions, and detected and characterized through mass-selected, infrared ion depletion spectroscopy-a strategy which exploits the extraordinary sensitivity of their vibrational signatures to the local hydrogen-bonded environment of their OH groups. The trial set of carbohydrates, alpha- and beta-anomers of glucose, galactose and fucose, reflects ligand fragments in naturally occurring protein-carbohydrate complexes and also allows an investigation of the effect of systematic structural changes, including the shape and extent of 'apolar' patches on the pyranose ring, removal of the OH on the exocyclic hydroxymethyl group, and removal of the aglycon. Bound complexes invariably form, establishing the general existence of intrinsic intermolecular potential minima. In most of the cases explored, comparison between recorded and computed vibrational spectra of the bound and free carbohydrates in the absence of solvent water molecules reveal that dispersion forces involving CH-pi interactions, which promote little if any distortion of the bound carbohydrate, predominate although complexes bound through specific OH-pi hydrogen-bonded interactions have also been identified. Since the complexes form at low temperatures in the absence of water, entropic contributions associated with the reorganization of surrounding water molecules, the essence of the proposed 'hydrophobic interaction', cannot contribute and other modes of binding drive the recognition of sugars by aromatic residues. Excitingly, some of the proposed structures mirror those found in naturally occurring protein-carbohydrate binding sites.     

Investigation of the interactions between the hydrophobic cavities of cyclodextrins and pullulanase

The effects of cyclodextrins and derivatives on the activity and structure of pullulanase were investigated in this study. Our results showed that cyclodextrins and derivatives decreased the activity of pullulanase. This decrease was attributed to the interaction between the hydrophobic cavities of cyclodextrins and pullulanase. The hydrophobic cavity was confirmed to encapsulate the groups of pullulanase molecules by the addition of competitive guests. The results obtained from fluorescence spectroscopy analysis showed that β-CD showed more efficient interactions with pullulanase molecules and the side chain groups of cyclodextrin significantly prevented the interaction between the hydrophobic cavities of β-CD and pullulanase molecules. These findings suggest that the geometric dimension of hydrophobic cavities was crucial for matching between cyclodextrins and pullulanase and steric hindrance caused by side chains led to the decrease of the interaction.     

The kinetics and molecular modeling of the complexation of tenoxicam with cyclodextrins in solution

The effect of cyclodextrins on photodegradation of tenoxicam (TEN) was studied at pH 4, 7 and 10. After 60 min of irradiation with UV light, the photodegradation was extensive. All cyclodextrins (alpha, beta, or gamma) stabilize TEN and reduce the rate of photodegradation. The largest effect of cyclodextrins is at pH 7. Molecular modeling results help to explain and manipulate the results. The results are discussed and compared with other results from previous studies.     

Paramagnetic NMR shift,spectroscopic and molecular modeling studies of lanthanide(III)-morin complexes

Studies on nine-coordinate lanthanide complexes of morin are described. The complexes were characterized by elemental analysis, molar conductance, UV–Vis spectra, IR spectra, thermal analysis and NMR spectra. Molecular modeling studies were also carried out. The complexes are non-electrolytes in DMSO. TGA showed anhydrous nature of the complexes. The electronic spectra of the complexes were recorded in methanol. ¹H NMR spectra of lanthanum, praseodymium, neodymium, samarium and dysprosium complexes have been studied in DMSO-d₆. The complexes do not dissociate in DMSO and retain their coordination. ¹H NMR spectra of paramagnetic and diamagnetic complexes exhibit downfield as well as upfield shifts of morin resonances that shows change in geometry during coordination.     

Half-sandwich ruthenium(II)-arene complexes: synthesis,spectroscopic studies,biological properties,and molecular modeling

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (¹H- and ¹³C-NMR, FT-IR), and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η⁶-arene)(XY)Cl](PF₆) where arene?=?benzene or toluene and XY?=?bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic “piano-stool” configuration of Ru(II)-arene complexes—as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η⁶-p-cymene)(Me₂dppz)Cl]PF₆ complex (Me₂dppz = 11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by molecular docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η⁶-benzene)(aip)Cl](PF₆) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6, and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

d-Xylose-based surfactants: Synthesis,characterization and molecular modeling studies

Pentose-derived surfactants were easily synthesized and fully characterized through classical analytical methods. The interfacial behaviors revealed the importance of both the length of the hydrophobic chain and the nature of the anomeric form. Finally, the spatial conformation of four xylosides was obtained by molecular modeling with software Hyperchem^® 4 using the semi-empirical method PM3, which demonstrated the role of hydrophobic interactions in the stability of the compounds.     

1H NMR spectroscopic study of the interaction between cyclodextrins and bicyclo[3.3.1]nonanes

The formation and structure of inclusion complexes of 2,6- and 2,9-substituted bicyclo[3.3.1]nonanes with- and-cyclodextrin (CD) has been investigated by high-resolution¹H NMR spectroscopy.- and-CD were found to form 1:1 inclusion complexes and the binding constants were estimated from titration studies. 2D ROESY experiments provided insight into the structure of the complexes.Presented in part at the 8th International Cyclodextrin Symposium, Budapest, March 30–April 2, 1996.     

Raman spectroscopic studies of terthiophenes for molecular electronics

The effect of thiol and selenol functionalization on the vibrational spectra and photochemical stability of terthiophene based molecular wires was investigated using surface-enhanced Raman scattering (SERS). The molecules were found to exhibit markedly different properties at the silver surface of the SERS substrate, despite having almost identical Raman spectra in solution and in the solid state. In contrast to terthiophene (3T), the bisthiolterthiophene (T3) and biselenol-terthiophene (Se3) molecules were stable against photoinduced structural changes when adsorbed to the metal surface at low concentrations. This indicates that the strong bonds to the silver surface, via S or Se terminal atoms, leads to a rapid decay of photoexcited states. Comparison with ab initio calculations shows that both T3 and Se3 bind with only one of the functional groups to the Ag surface.     

Exploring the binding mechanism of dihydropyrimidinones to human serum albumin: spectroscopic and molecular modeling techniques

The binding mechanism of molecular interaction between 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (a dihydropyrimidinones derivative, EMPD) and human serum albumin (HSA) was studied using spectroscopic methods and modeling technique. The quenching mechanism was investigated in terms of the binding constants and the basic thermodynamic parameters. The results of spectroscopic measurements suggested that EMPD have a strong ability to quench the intrinsic fluorescence of HSA through static quenching procedure. The drug-protein complex was stabilized by hydrophobic forces and hydrogen bonding as indicated from the thermodynamic parameters and synchronous fluorescence spectra, which was consistent with the results of molecular docking and accessible surface area calculation. Competitive experiments indicated that a displacement of warfarin by EMPD, which revealed that the binding site of EMPD to HSA was located at the subdomains IIA. The distance between the donor and the acceptor was 4.85nm as estimated according to F?rster's theory of non-radiation energy transfer. The effect of metal ions on the binding constants was also investigated. The results indicated that the binding constants between EMPD and HSA increased in the presence of common metal ions.     

Understanding the performance of biomaterials through molecular modeling: crossing the bridge between their intrinsic properties and the surface adsorption of proteins

Molecular modeling and computer simulations can yield significant new insight at the atomistic level about the performance of biomaterials in a biological environment. In this paper, we review our approach to a consistent theoretical picture of the bulk and surface properties of biomaterials. The predicted properties do encompass in particular the mechanical behavior and the surface hydration of these materials, and the surface physisorption of proteins, or polypeptides in general. The behavior of nanomaterials such as the carbon allotropes, nanotubes and fullerenes, in a biological environment is also briefly considered.     

Understanding the interactions between tris(pentafluoroethyl)-trifluorophosphate-based ionic liquid and small molecules from molecular dynamics simulation

Tris(pentafluoroethyl)trifluorophosphate ([FEP])-based ionic liquids have been widely applied in many fields. For better understanding the properties of [FEP]-based ionic liquids, the interactions between 1-hexyl-3-methylimidazolium ([hmim])[FEP] and small molecules were investigated by molecular dynamics simulations in this work. The small molecules are water, methanol and dimethyl ether. The united-atom (UA) force fields were proposed for methanol and dimethyl ether based on AMBER force field. The densities, enthalpies of vaporization, excess molar properties, and diffusion coefficients of the mixtures were calculated, as well as the microscopic structures characterized by radial distribution functions. Both of the results of the excess energies and microscopic properties show that the strongest interaction is between [hmim][FEP] and dimethyl ether, whereas the interaction between [hmim][FEP] and water is the weakest. Moreover, [hmim][FEP] is more hydrophobic than [hmim] hexafluorophosphate ([PF6]), and the three solutes are mainly distributed around [FEP] anion.     

Molecular modeling and spectroscopic studies on the binding of guaiacol to human immunoglobulin

The fluorogenic property of guaiacol was exploited for the first time to analyze the interaction with target protein as a probe by molecular modeling, fluorescence, circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy. Molecular docking was performed to reveal the possible binding mode or mechanism and suggested that guaiacol can strongly bind to human immu- noglobulin (HIgG). It is considered that guaiacol binds to HIgG mainly by a hydrophobic interaction and there are two hydrogen bond interactions between the drug and the residues LEU 80 and ASP 65, which is in good agreement with the results from the experimental thermodynamic parameters (the enthalpy change △H0 and the entropy change △S0 were calculated to be 65.55 kJ·mol-1 and 132.95 J·mol-1·K-1 according to the Vant’ Hoff equation). Data obtained by the fluorescence spectroscopy indicated that binding of guaiacol with HIgG leads to dramatic enhancement in the fluorescence emission intensity along with significant occurrence of efficient Frster resonance energy transfer (FRET) from the residue of HIgG to the protein bound guaiacol. From the low value of fluorescence anisotropy (r = 0.06), it is argued that the probe molecule is located in the motionally unrestricted environment of the protein. The alterations of protein’s secondary structure in the presence of guaiacol in aqueous solution were quantitatively calculated by the evidences from FT-IR and CD spectroscopes.