The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?

Reductionism is alive and well in drug-discovery research. In that tradition, we continually improve experimental and computational methods for studying smaller and smaller aspects of biological systems. Although significant improvements continue to be made, are our efforts too narrowly focused? Suppose all error could be removed from these methods, would we then understand biological systems sufficiently well to design effective drugs? Currently, almost all drug research focuses on single targets. Should the process be expanded to include multiple targets? Recent efforts in this direction have lead to the emerging field of polypharmacology. This appears to be a move in the right direction, but how much polypharmacology is enough? As the complexity of the processes underlying polypharmacology increase will we be able to understand them and their inter-relationships? Is “new” mathematics unfamiliar in much of physics and chemistry research needed to accomplish this task? A number of these questions will be addressed in this paper, which focuses on issues and questions not answers to the drug-discovery conundrum.     

Magnetism and the biradicaloid character of π-aromatic and antiaromatic systems in a strong magnetic field

The previously developed scheme of the full configuration interaction for magnetic perturbations of π systems is transformed into a scheme for calculations in the finite field. It helps create “magnetic portraits” of molecules, reflecting the essentially non-linear behavior of conjugated systems in a strong field. In particular, possible latent paramagnetism of aromatic systems and correspondingly latent diamagnetism of antiaromatic ones is easily detected. The degree of the π electron shell openness as well as the singlet-triplet splitting in the field are evaluated. From the data obtained it follows that in the strong magnetic field an aromatic molecule becomes as a rule biradicaloid and non-aromatic. Accordingly, an antiaromatic system dramatically reduces its initial biradicaloid character and thus loses its antiaromaticity.     

The importance of conformational search: a test case on the catalytic cycle of the Suzuki�CMiyaura cross-coupling

Conformational diversity is an often neglected aspect in computational studies of transition metal complexes, even when relatively large systems are involved. The importance of conformational searches is illustrated through the analysis of the errors that could be caused by a wrong choice of conformers in the computational study of the Suzuki?CMiyaura cross-coupling between CH₂=CHBr and CH₂=CHB(OH)₂ catalyzed by [(PPh₃)₂Pd] or [(P(i-Pr)₃)₂Pd]. The error bars associated with conformational diversity of the [(PPh₃)₂Pd] catalyst range between 0.3 and 6.7?kcal/mol, the values growing up to 11.4?kcal/mol when the more flexible [(P(i-Pr)₃)₂Pd] catalyst is considered.     

M. S. Tswett and the discovery of chromatography II: Completion of the development of chromatography (1903–1910)

Summary In this, the second part of our review we continue the discussion of the activities of M. S. Tswett related to the development of chromatography. We shall deal here with his activities in Warsaw from 1903 onwards, resulting in his fundamental twin papers of 1906 and his book of 1910, summarizing all his activities related to the investigation of plant pigments and to the development of chromatography. Finally, a few special questions related to Tswett's work shall be discussed.For Part I, seeChromatographia 35, 223 (1993). References are numbered through.     

Half-metallicity and spin-contamination of the electronic ground state of graphene nanoribbons and related systems: an impossible compromise?

An analysis using the formalism of crystalline orbitals for extended systems with periodicity in one dimension demonstrates that any antiferromagnetic and half-metallic spin-polarization of the edge states in n-acenes, and more generally in zigzag graphene nanoislands and nanoribbons of finite width, would imply a spin contamination S(2) that increases proportionally to system size, in sharp and clear contradiction with the implications of Lieb's theorem for compensated bipartite lattices and the expected value for a singlet (S = 0) electronic ground state. Verifications on naphthalene, larger n-acenes (n = 3-10) and rectangular nanographene islands of increasing size, as well as a comparison using unrestricted Hartree-Fock theory along with basis sets of improving quality against various many-body treatments demonstrate altogether that antiferromagnetism and half-metallicity in extended graphene nanoribbons will be quenched by an exact treatment of electron correlation, at the confines of non-relativistic many-body quantum mechanics. Indeed, for singlet states, symmetry-breakings in spin-densities are necessarily the outcome of a too approximate treatment of static and dynamic electron correlation in single-determinantal approaches, such as unrestricted Hartree-Fock or Density Functional Theory. In this context, such as the size-extensive spin-contamination to which it relates, half-metallicity is thus nothing else than a methodological artefact.     

Determination of Quinine and Doxycycline in Rat Plasma by LC�CMS�CMS: Application to a Pharmacokinetic Study

A fast, sensitive, and specific LC?CMS?CMS method for determination of quinine (QN) and doxycycline (DOX) in rat plasma has been developed and validated. QN, DOX, and cimetidine (internal standard, IS) were extracted from the plasma by protein precipitation. The compounds were separated on a C₁₈ column with methanol?C0.1% aqueous formic acid 70:30 (v/v) as mobile phase at a flow rate of 0.5 mL min^?1 (split 1:3). Detection was by positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode, monitoring the transitions 325.0 ?? 307.0, 445.0 ?? 428.1, and 252.8 ?? 159.0, for QN, DOX, and IS, respectively. The analysis was carried out in 2.0 min and the method was linear in the plasma concentration range 5?C5,000 ng mL^?1. The mean extraction recoveries for QN, DOX, and IS from plasma were 89.4, 90.5, and 86.3%, respectively. The method was validated for linearity, precision, accuracy, specificity, and stability; the results obtained were within the acceptable range. The proposed method was successfully applied to the determination of QN and DOX in rat plasma samples to support pharmacokinetic studies.     

The first spiroconjugated TTF- and TCNQ-type molecules: a new class of electroactive systems?

[Structure: see text] Spiroconjugated TTF-type electron donors (13a-c) and TCNQ-type electron acceptors (10, 11) have been prepared from spiroquinone 9. Cyclic voltammetry reveals a relatively weak accepting ability for 10 and 11, and a strong electron-donor character for 13a-c. Whereas the spiroconjugation introduces a destabilization of the LUMO for compounds 9-11, the opposite is observed for compound 13, thus justifying the redox potential values.     

Chemical reactivity of the imidazole: a semblance of pyridine and pyrrole?

It has been suggested that pyridine and pyrrole could be patterns for imidazole reactivity studies due to the amine (-NH-) and aza (-N═) nitrogen atoms. The analyses of the local and global electronic indexes prove and quantify that imidazole has an intermediate analogy between pyrrole and pyridine.     

Detection of Nandrolone and Boldenone Abuse in the Ovine by GC�CMS�CMS

Under European legislation, the use of anabolic steroids as growth promoters in meat production is prohibited. Currently, there is no internationally accepted method used for the detection of the potentially endogenous steroids nandrolone and boldenone in the ovine. In the current study, a multi-residue GC?CMS?CMS-based urinary assay has been validated for boldenone as well as the nandrolone metabolites 5??-estrane-3??,17??-diol and epinandrolone. Using a standard addition calibration line approach in pooled bovine urine, the method was linear between the endogenous concentrations and those augmented with 6,000 pg mL^?1. The method was then applied to populations of wether (n = 242) and ewe (n = 237) ovine animals in order to establish urinary thresholds for detecting nandrolone and boldenone abuse. A statistical model (the Chebyshev inequality) was used to produce threshold concentrations for each analyte. Adjustment of the nandrolone metabolite data for specific gravity, a measure of the hydration status of the animal, allowed the effective thresholds to be reduced; potentially leading to a lower number of false positives. Furthermore, the proposed epinandrolone confirmatory thresholds (38,628 and 57,950 pg mL^?1 in wethers and ewes, respectively) were found to be effective in detecting abuse of nandrolone for at least 1 month post-dose of this steroid. However, further studies would be required to assess the efficacy of the proposed boldenone confirmatory thresholds (19,857 and 56,080 pg mL^?1 in wethers and ewes, respectively) since data on its excretion following administration to the ovine are lacking.     

Can we predict the spreading of a two-liquid system from the spreading of the corresponding liquid-air systems?

We present new data obtained from the spreading of a series of oil droplets, on top of a hydrophobic grafted silicon substrate, in air and immersed in water. We follow the contact angle and radius dynamics of hexane, dodecane, hexadecane, dibutyl phthalate, and squalane from the first milliseconds to approximately 1 s. Analysis of the images allows us to make several hundred contact angle and droplet radius measurements with great accuracy. The G-Dyna (Seveno et al. Langmuir 2010, 25, 13034) software is then used to fit the data with one of the wetting theories, the molecular-kinetic theory (MKT) (Blake et al. J. Colloid Interface Sci.1969, 30, 421), which takes into account the dissipation at the three-phase zone at the contact line. This theory allows us to extract the coefficient of friction of the contact line, which expresses the relationship between the driving force, that is, the unbalanced Young force, and the contact-line velocity V. It is first shown that the MKT is appropriate to describe the experimental data and then that the contact-line friction is a linear function of the viscosity as theoretically predicted. This is checked for oil-air and oil-water systems. A linear relation between the contact-line friction measured in oil-water systems and the contact-line frictions of the parent single liquid system seems plausible. To the best of our knowledge, this is the first trial to establish a link between the dynamics of wetting in liquid-liquid and in liquid-air systems.     

HPLC�CMS�CMS for the Simultaneous Determination of Atorvastatin and Amlodipine in Plasma of Hypertensive Patients

Combination drug products containing amlodipine and atorvastatin are widely marketed and used in the treatment of concomitant hypertension and dyslipidemia. A rapid, simple and sensitive high performance liquid chromatography?Ctandem mass spectrometry (HPLC?CMS?CMS) method for determination of atorvastatin and amlodipine in plasma of hypertensive patients has been developed and validated to be used for therapeutic drug monitoring. The plasma samples were subjected to methanol protein precipitation. Chromatographic separation was performed on a C18 column using a gradient elution. The mobile phase consisted of 0.1% of formic acid in water and 0.1% of formic acid in acetonitrile and was pumped at a flow rate of 0.4 mL min^?1. Detection of analytes was achieved by tandem mass spectrometry with electrospray ionization (ESI) interface in positive ion mode. The calibration curves were linear over the range of 0.46?C1,000 ng mL^?1. The intra- and inter-day precisions were within 12.2%, while the accuracy ranged from 92.7 to 108.1%. The validated LC?CMS?CMS method was successfully applied for the determination of atorvastatin and amlodipine in plasma of hypertensive patients.     

Effect of a magnetic field on the rheological properties of the systems hydroxypropyl cellulose–ethanol and hydroxypropyl cellulose–dimethyl sulfoxide

With the use of viscometry, the cloud-point method, polarization microscopy, the turbidity-spectrum method, and a polarization photoelectric apparatus, the relaxation pattern of the rheological behaviors, phase transitions, and structures of the systems hydroxypropyl cellulose–ethanol and hydroxypropyl cellulose–dimethyl sulfoxide are studied. The regions of existence of isotropic and anisotropic phases and the concentration dependence of the sizes of supramolecular particles are determined. It is found that a magnetic field increases the viscosities of solutions. The concentration dependences of viscosity and particle size are described by curves with maxima.     

Thermodynamics of the solvation and phase distributions of 2,2′-dipyridyl in acetonitrile-DMSO-hexane and methanol-DMSO-hexane systems

The Gibbs energies of 2,2′-dipyridyl when transferred from dimethyl sulfoxide to its mixtures with acetonitrile and methanol are determined from the distribution of substance between immiscible phases. It is found that moving from dimethyl sulfoxide to acetonitrile and methanol weakens the solvation of 2,2′-dipyridyl due to a change in the solvation of amino groups and the hydrocarbon substituent, which is reflected in a reduction in the entropy component of the Gibbs energy.     

The hierarchy of localization basins: a tool for the understanding of chemical bonding exemplified by the analysis of the VOx and VOx+ (x=1–4) systems

The hierarchy of the electron localization basins is a powerful tool of analysis of the bonding in molecules and solids within the “elfological” framework. It is a generalization of the molecular isodensity contour analysis originally proposed by Mezey. In this approach the basins are ordered with respect to the electron localization function values at the critical points which determine the reduction of the reducible localization domains. The procedure enabling the corresponding tree diagrams to be built is described and it is shown how the method can be used as a generator of mathematical definitions of chemical concepts. The possibility offered by this simple tool is illustrated by a study of the VO _x and VO _x ⁺ (x=1–4) oxides in their ground state and in some excited states. Received: 20 July 2000 / Accepted: 20 October 2000 / Published online: 23 January 2001     

Determination of Pilocarpine in Human Plasma by LC�CAPCI�CMS�CMS and Application to a Pharmacokinetic Study

A sensitive, specific and rapid high performance liquid chromatography?Catmospheric pressure chemical ionization source-tandem mass spectrometry (LC-APCI-MS-MS) method for the determination of pilocarpine in human plasma was developed and validated. The method is based on liquid?Cliquid extraction, followed by a reversed-phase liquid chromatographic separation, and detected by means of tandem mass spectrometry. The linear calibration curve covered a concentration range of 2?C500 ??g L^?1. The intra- and inter-day precisions for pilocarpine were <10% and the accuracies were between 90 and 110%. The method was applied successfully to a pharmacokinetic study involving 20 healthy Chinese male volunteers after oral administration of 6 mg pilocarpine.     

Preparation of sol�Cgel hybrid materials from ��-methacryloxypropyltrimethoxysilane and tetramethyl orthosilicate: study of the hydrolysis and condensation reactions

Organic?Cinorganic hybrid materials suitable for the development of sol?Cgel coatings for metallic surfaces were prepared by hydrolysis and condensation of ??-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethyl orthosilicate (TMOS). The hydrolysis of MAPTMS/TMOS was carried out in an ethanol/water solution. The prehydrolysis stage of MAPTMS/TMOS system was monitored by Fourier transform infrared spectroscopy (FTIR) and liquid-state ²⁹Si and ¹³C nuclear magnetic resonance (²⁹Si and ¹³C NMR). FTIR analysis indicated that the hydrolysis of MAPTMS/TMOS was accomplished as far as the (SiOMe) band corresponding to unhydrolyzed silane disappeared. The concentration of the alkoxy groups and the extent of self-condensation of mono-, di-, and trisubstituted siloxanes (T species) in the sol were estimated by using liquid-state ²⁹Si NMR spectroscopy. The hydrolysis of the prepared sol was also evaluated by liquid-state ¹³C NMR spectroscopy. The results indicated that under the adopted synthesis strategy conditions, the hydrolysis process requires 4?h to be completed.     

On the Circulation Structure and Formation Mechanism of the Cold Water Mass of the Yellow Sea (Ⅰ)——Zero-order Solution and Circulation Structure

A series of studies have been made on the circulation structure and the responsible mechanisms related to the Cold Water Mass of the Yellow Sea. From the present model governing the nonlinear thermally driven circulation in shallow seas, some complete analytical solutions of temperature and velocity components have been obtained in this paper by solving the coupled equations of motion and heat conduction. The results demonstrate that the wind-induced stirring and the tidal mixing are all responsible for the termal structure formation of Cold Water Mass. The computed vertical convection (u-w) develops only within a thin layer (called "a current shell" here) in the vicinity of thermocline while the deeper layer remains almost motionless. This current structure represents well the maintenance mechanisms of thermocline or the Cold Watermass during the summer.