Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding

The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors:

• •Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.
• •MM optimization gives a very different configuration to the QM optimization for nilotinib, whereas the imatinib ion gives similar configurations
• •Solvation energies are a major component of the overall binding energy. The QM based solvent model (PCM/SMD) gives different values from those used in the implicit PBSA solvent MM models. A major error in inhibitor—kinase binding lies in the non-polar solvation terms.
• •Solvent transfer free energies and the required empirical solvent accessible surface area factors for nilotinib and imatinib ion to give the transfer free energies have been reverse calculated. These values differ from those used in the MM PBSA studies.
• •An intertwined desolvation—conformational binding selectivity process is a balance of thermodynamic desolvation and intramolecular conformational kinetic control.
• •The configurational entropies (TΔS) are minor error sources.

     

Physical Properties of Highly Active Liquor Containing Molybdate Solids

The reprocessing of irradiated nuclear fuel at Sellafield produces a nitric acid based Highly Active Liquor (HAL) waste. The liquor, containing fission products and process additives, is concentrated in an evaporator in order to reduce the volume and is then stored in Highly Active Storage Tanks (HASTs) prior to vitrification. Caesium phosphomolybdate (CPM) is precipitated during the evaporation process and can convert to zirconium molybdate (ZM) during storage.During Post Operational Clean Out (POCO) of the HASTs, it is expected that their highly active content will be reduced by repeated cycles of washing using nitric acid and other reagents. Initial washings are likely to have a chemical composition comparable to concentrated HAL, becoming more dilute during the wash-out process. It is expected that the wash-out process will also recover significant quantities of molybdate solids (ZM, CPM or a mixture) from the HASTs.In order to determine the processing challenges from such washings during POCO, the physical properties of varying concentrations of non-active HAL simulants containing molybdate solids have recently been measured by the UK's National Nuclear Laboratory. The following measurements are presented and discussed:

• •Particle size distribution
• •Density
• •Settling behaviour of solids
• •Voidage of settled sediment beds
• •Viscosity
• •Yield stress
• •Influence of ZM morphology on physical properties

     

Latest Developments in Proton Conductors

Solid proton conductors are receiving considerable attention, stimulated by the need of pollution control and with the objective to develop future microprotonics. The latest striking developments in the study of proton conductors are presented:

• i)Hydrogen containing perovskites, with a discussion of the nature and location of hydrogen inprotonic and electronic high-temperature superconductors;
• ii)Novel forms of hydrogen in disordered and mixed conductors, with the problems of the vibrational proton transfer assistance assumed by some authors and the independent proton dynamics evidenced by inelastic neutron scattering;
• iii)Frequency dependent conductivity and dielectric relaxation, including thermally stimulated current experiments in hydrated synthetic and biological gels (seeds);
• iv)Proton conducting membranes as candidates to replace Nafion®-like materials in H₂ (methanol) fuel cells.

     

Calorimetric studies of CeCu AND CeMgCu alloys

Using different calorimeters, the following measurements have been carried out.

• 1.(i) The integral enthalpies of mixing of CeCu binary and some CeMgCu ternary liquid alloys,
• 2.(ii) The enthalpy of formation and the enthalpy of melting of the intermetallic compound CeCu₂.
• 3.(iii) The heat content of solid and liquid CeCu₂.

The observed concentration and temperature dependence of the measured values of the enthalpies of mixing as well as the glass-forming abilities of these alloys are explained on the basis of an association model.     

Effects of static magnetic fields of erythrocyte rheology

The orientation of normal erythrocytes in a uniform static magnetic field (8 T maximum) has been investigated microscopically and photometrically.

• 1.(1) The intact erythrocytes were oriented with their disk planes parallel to the magnetic field because of the diamagnetism of the cell membrane components, particularly the transmembrane proteins (e.g., Band III, glycopholin) and the lipid bilayer.
• 2.(2) In contrast, the glutaraldehyde-fixed erythrocytes were oriented perpendicular to the field, perhaps because of the paramagnetism of the membrane-bound methemoglobin.
• 3.(3) The orientation was established within 5 s in a dilute suspension (5 × 10³cells μl⁻¹) as estimated from the change in light scattering after exposure to the magnetic field.

     

Synthese et caracterisation de fluorotellurates IV alcalins et d'ammonium partie I. Etude du pentafluorotellurate IV de lithium LiTeF5

Lithium pentafluorotellurate (IV) LiTeF₅ has been prepared by different methods:

• •slow evaporation of a 1/1 mixture of lithium fluoride and tellurium dioxide or tellurium tetrachloride in anhydrous hydrogen fluoride,
• •heating a 1/1 mixture of lithium fluoride and tellurium tetrafluoride. LiTeF₅ is orthorhombic

(a = 9,52 Å b = 9,12 Å c = 11, 60 Å)     

New experimental set-ups for studying nanoconfined water on the AILES beamline at SOLEIL

Three ensembles designed to investigate condensed matter in complex environments have been developed recently on the AILES beamline at SOLEIL. They have been exploited for studies aiming at understanding the properties of water molecules and their network in various confining systems, namely:

• -a hydration and temperature-controlled cell for the study of water confined in nanoporous Vycor,
• -a high pressure set-up allowing the study of the evolution of water molecules network trapped in Faujasite through the pressure-induced amorphisation of the matrix material,
• -a temperature resolved electrochemical cell used to record FIR difference spectra of metalloproteins interacting with water molecules.

By combining the high infrared flux and collimation of the AILES beamline with these optimized sample environments, it is possible to measure the infrared and THz spectra for minute quantities of samples in precise physical conditions.     

Application of radiation technology in biomedical materials; Fundamentals and applied

• 1.1) IMMOBILIZATION OF HEMOGLOBIN Hemoglobin has been immobilized into Poly Hema Matrix. To increase, Mechanical resistance, at first, CO was coodinated, after immobilization CO was eliminated by photo illumination by visible light from a W lamp and then O₂ was introduced. Oxygencoordiation ability was not damaged by immobilization.
• 2.2) REDUCTION MECHANISM OF ENZYME BY THE USE OF PULSE RADIOLYSIS Elementary process of Reduction Mechanism of Myoglobin, Hemoglobin, HRP and Cytochrome Oxidase were investigated in the time range of μsec≈nsec. In the of Cytochrome Oxidase, these are 4 metal ions inside of the Enzyme. The exact step of reduction of this enzyme was elucidated

.     

On ion-pair photoseparation and recombination in micellar aggregates

Perylene (Pe) and tetramethylbenzidine (TMB) have been photoionized under continuous or laser pulse excitation in cationic (Mi⁺), neutral (Mi⁰) or anionic micelles (Mi^-). In the latter case, Mi^- composed of sodium dodecyl sulfate (SDS) surfactant molecules have been swollen upon the addition of various hydrocarbons and the interfacial electric potential ΔΨ modified by electrolyte addition.From previous and present data, the following conclusions can be drawn:

• •(a) Intramicellar ultrafast geminate recombinations are promoted by increasing the micellar volume but counteracted when high electron mobility values characterize the swelling agent;
• •(b) Recombinations involving the hydrated electron ρ^-_aq appear to be suppressed in negatively as well as in positively charged Mi and to occur in Mi⁰ to an extent depending upon the chromophore cation;
• •(c) The overall photoionization yield ø_ion of Pe or TMB is found to increase linearly as ΔΨ becomes more negative; such ΔΨ variation is shown to affect ø_ion through the primary electron ejection stage though the ionization threshold energy does not seem to be appreciably modified;
• •(d) For Mi^- aggregates, the photoionization efficiency curves ø_ion=f(λ) show a linear dependence on the photon excess energy in the threshold region; within such an energy range, the ø_ion(λ) curves would thus approximate the variation with λ of a primary ionization yield of the solute;
• •(e) As a corollary, it may be suggested that the shape of the ø_ion(λ) curves relative to homogeneous liquid solutions would be essentially governed by solute cation-ρ^-_solv recombination reactions.

     

N–H stretching frequencies and the conformation of substituted ureas: an ab initio MO study

The dependence of N–H stretching-mode frequencies in representative di- and trialkyl ureas on the conformational state of the ureido group has been studied by ab initio MO calculations using HF/3-21G and HF/6-31G** basis sets. The molecules studied were 1,3-dimethylurea, 1-methyl-3,3-dimethylurea and 1-methyl-3,3-di-iso-propylurea. The principal conclusions from the ab initio results are:

• 1.the trans–trans conformer (N–H bonds trans to the CO bond) has N–H stretching bands with about 20–30 cm⁻¹ higher frequency than the respective cis–cis structure, in accord with earlier literature assignments based on experimental data;
• 2.the N–H stretching frequency interval in tri-substituted ureas is 15–20 cm⁻¹ higher than the N–H band position in the 1,3-disubstituted molecule studied, the effect being determined mostly by the higher N–H stretching force constant;
• 3.in the absence of the steric hindrance the stable rotameric forms of the ureido grouping are almost planar at HF/3-21G level of calculations, while HF/6-31G** calculations predict a slightly pyramidal structure at the nitrogen atoms in the trans–trans conformer;
• 4.in 1-methyl-3,3-di-iso-propylurea the steric influence of the two bulky iso-propyl groups cause a deviation from planarity of the N–H bond. The non-planar conformation is accompanied by a shift of the N–H stretching mode frequency towards higher values; and
• 5.the variations of the theoretically estimated N–H stretching-mode frequencies appear to be principally determined by changes in the N–H stretching force constants in the different molecules.

© 1997 Elsevier Science B.V.     

Synthese et caracterisation de fluorotellurates IV alcalins et d'ammonium partie II: Etude des fluorotellurates d'ammonium NH4TeF5 et (NH4)2TeF6

New methods of synthesis:

• •reaction of aqueous or anhydrous HF with TeO₂ and NH₄F or NH₄HF₂, with (NH₄)₂TeCl₆
• •reaction of TeF₄ with NH₄F or NH₄HF₂
• •reaction of NH₄HF₂ with TeO₂

have been investigated for NH₄TeF₅ and a new compound (NH₄)₂TeF₆. The resulting compounds have been analysed and characterized.     

899 — A potentiometric study on the redox properties of hemoglobin from Camelus dromedarius

A potentiometric study of the redox properties of hemoglobin from Camelus dromedarius has been performed, with the aim of having a better insight in the structure-function relationships of this protein; data on human hemoglobin have been included for comparative purposes. Analysis of the experimental data has shown:

• 1.the existence of intermediate conformers (neither R nor T) in the oxidized form of dromedary hemoglobin;
• 2.the amino acid groups involved in the oxidation Bohr effect of dromedary and human hemoglobins are likely to be the same; thus, only invariant amino acid residues seem to be involved in this effect.

     

Fourier transform infrared spectroscopic studies of the secondary structure and thermal denaturation of CaATPase from rabbit skeletal muscle

Fourier transform i.r. spectroscopy has been used to monitor structural alterations induced by thermal denaturation of the intrinsic membrane protein CaATPase in aqueous media. The protein has been isolated, purified and studied in five forms:

• 1.(i) In its native lipid environment after isolation from rabbit sarcoplasmic reticulum, both in H₂O and D₂O suspensions.
• 2.(ii) After both mild and extensive tryptic digestion has cleaved those residues external to the membrane bilayer.
• 3.(iii) Reconstituted in vesicle form with bovine brain sphingomyelin.

Fourier deconvolution techniques have been used to enhance the resolution of the intrinsically overlapped Amide I and Amide II spectral regions. Large spectral alterations apparent in the deconvoluted spectra occur in these regions upon thermal denaturation of the protein which are consistent with the formation of a large proportion of β-antiparallel sheet form. The alteration parallels the loss in ATPase activity. A mild tryptic digestion increases slightly the proportion of α-helix and/or random coil secondary structure. A thermal transition to a form containing a high proportion of β structure is still evident. Extensive tryptic digestion nearly abolishes the alpha helical plus random coil secondary structure, while producing a high proportion of β form which is resistant to further thermally induced structural alterations.Studies of CaATPase reconstituted into vesicles with bovine brain sphingomyelin reveal a higher proportion of β structure than the native enzyme, with further introduction of β structure on thermal denaturation. Both the utility of deconvolution techniques and the necessity for caution in their application are apparent from the current experiments.     

Conformational transitions in the regulation of cytochrome c oxidase activity

Oxidation of cytochrome c, catalyzed by cytochrome oxidase embedded in artificial liposomes of high respiratory control ratio (between 5 and 9.5), has been studied by rapid mixing techniques, under which conditions the enzyme undergoes a limited number of turnovers (from 1 to 5). The time course of the reaction could be satisfactorily simulated by a procedure derived from the concerted two-state model of Monod-Wyman-Changeux.The bulk of data and the novel analytical approach confirm the proposal that cytochrome oxidase undergoes a transition from a fast-reacting to a slow-reacting form as a consequence of the electrochemical gradient built up across the phospholipidic bilayer, and substantiate the idea that the conformational change:

• •occurs as an all-or-none process after about one turnover irrespective of the molar ratio between substrate and enzyme, and
• •is not immediately correlated to the other well known transition from the resting to the pulsed form of the enzyme.

     

Photodissociation of gas-phase I−3: product branching in the visible and UV regions

Photodissociation of the gas-phase triiodide anion, I⁻₃, was investigated using photofragment mass spectrometry. The photofragment yield (PFY) and photoproduct branching fractions were determined from the observed mass spectra in the wavelength range 270–540 nm (2.3–4.6 eV). The measurement revealed that:

• 1.I⁻₃ photodissociation occurs with the production of I⁻ and I⁻₂ fragments in the whole energy range studied,
• 2.the branching ratio of I⁻ versus I⁻₂ production depends strongly on the excitation energy.

These experimental findings clearly demonstrate the nonadiabatic nature of the I⁻₃ photodissociation dynamics.     

The development of heat flow calorimetry as a tool for process optimization and process safety

Classical thermo-analytical micro methods (DTA, DSC) are still very useful for process work, but medium scale instruments based on heat flow measurement are attaining an increasingly important role in this domain. As in many areas, development of reaction calorimetry for industrial applications was driven by needs and by available means (technical capabilities). The needs have been fairly constant over the past decades. There are data needs:

Reaction rates

Heat release rates

Heat of desired reactions and decompositions

Heat capacities and heat transfer capacities

It took the specialists of calorimetry a long time to recognize and to accept the operational needs, namely:

Working under controlled temperature conditions (constant temperature, temperature ramps)

Adding components during runs (continuously or in portions)

Simulation of industrial mixing conditions

The main driving force for the development of process oriented calorimetric instruments was the evolution of electronic hardware which made the control of heat flow on a (non micro) laboratory scale easy. The paper gives an overview on the principles of heat flow control and reviews the developments of the fifties and sixties, when the matching of heat flow with heat release by reactions was the goal. With the advent of fast and powerful laptop computers, the focus has shifted. Now, the deduction of true heat release rates from signals which may be badly distorted, is the goal. Some recent developments are reviewed and the hope is expressed that calorimetric equipment, inexpensive enough to be affordable for every laboratory engaged in process work, will be available soon.     

Investigation of the CeFe binary system

The CeFe binary system was investigated and an FeCe binary phase diagram was proposed. This system consists of

• 1.(i) two peritectic reactions, γ-Fe + L → Ce₂Fe₁₇ and Ce₂Fe₁₇ + L → CeFe₂, occurring isothermally at 1063°C and 925°C respectively;
• 2.(ii) a eutectic reaction, L → CeFe₂ + Ce, occurring isothermally at 592°C with eutectic containing 83.3 at.% Ce (92.6 wt.% Ce);
• 3.(iii) a peritectoid reaction, γ-Fe + Ce₂Fe₁₇ → α-Fe(Ce), occurring isothermally at 922 °C.

The solid solubility of cerium in iron in the temperature range 850–900 °C was found to be less than 0.04 at.% (0.1 wt.%). The Curie temperature of α-Fe(Ce) was slightly lowered with increasing cerium content in solid solution.