Virtual darwinian drug design: QSAR inverse problem, virtual combinatorial chemistry, and computational screening

The generation of diversity and its further selection by an external system is a common mechanism for the evolution of the living species and for the current drug design methods. This assumption allows us to label the methods based on generation and selection of molecular diversity as "Darwinian" ones, and to distinguish them from the structure-based, structure-modulation approaches. An example of a Darwinian method is the inverse QSAR. It consists of the computational generation of candidate chemical structures and their selection according to a previously established QSAR model. New trends in the field of combinatorial chemical syntheses comprise the concepts of virtual combinatorial synthesis and virtual or computational screening. Virtual combinatorial synthesis, closely related to inverse QSAR, can be defined as the computational simulation of the generation of new chemical structures by using a combinatorial strategy to generate a virtual library. Virtual screening is the selection of chemical structures having potential desirable properties from a database or virtual library in order to be synthesized and assayed. This review is mainly focused on graph theoretical drug design approaches, but a survey with key references is provided that covers other simulation methods.     

Chromatographic characterization of adult and foetal rat insulin

Foetal rat pancreatic rudiments explanted on day 14 of gestation were grown in organ culture in medium enriched with amino acids. The size of the insulin granules was increased, resulting in an insulin granule volume fraction greater than the volume fraction measured in pancreas grown in vivo. The pancreas was extracted and the insulin compared. Serial dilution curves of extracts of adult pancreas and pancreas grown in vitro are parallel in the insulin radioimmunoassay, whereas extracts of pancreas of foetus developing in utero appear immunologically different. Adult and foetal rat insulin (in utero) were purified using chromatography on OPTI UP C12, cellulose thin-layer chromatography plates, cellulose acetate foil electrophoresis and finally high-performance liquid chromatography. The ratio of insulin I to insulin II was found to be 1.5 for the adult and 2.7 for the foetus. These results show that there is an unequal expression of the two non-allelic genes controlling insulin biosynthesis in foetal and adult rat pancreas.     

Synthesis and characterization of MCM-48 tubular membranes

MCM-48 membranes have been prepared on alumina supports of different pore sizes. A battery of characterization techniques has been used to study the physical properties and the quality of the membranes prepared. The highest quality membranes were prepared on supports with pore size of up to 60 nm. The MCM-48 membranes were tested in the separation of gas phase mixtures and a cyclohexane/O₂ selectivity higher than 270 was obtained. The selective separation of organic compounds from inert components is a result of the cooperative effects of capillary condensation in MCM-48 pores and of the specific interactions of the permeating compounds and the membrane material.     

Preparation and sedimentation behavior in magnetic fields of magnetite-covered clay particles

This work is devoted to the preparation of magnetite-covered clay particles in aqueous medium. For this purpose, magnetite nanoparticles were synthesized by a coprecipitation method. These magnetic particles are adhered to sodium montmorillonite (NaMt) particles in aqueous suspensions of both materials, by appropriate control of the electrolyte concentrations. The best condition to produce such heteroaggregation corresponds to acid pH and approximately 1 mol/L ionic strength, when the electrokinetic potentials (zeta-potential) of both NaMt and Fe3O4 particles have high enough and opposite sign, as demonstrated from electrophoresis measurements. When a layer of magnetite re-covers the clay particles, the application of an external magnetic field induces a magnetic moment in clay-magnetite particles parallel to the external magnetic flux density. The sedimentation behavior of such magnetic particles is studied in the absence or presence of an external magnetic field in a vertical direction. The whole sedimentation behavior is also strongly affected by the formation of big flocculi in the suspensions under the action of internal colloidal interactions. van der Waals and dipole-dipole magnetic attractions between magnetite-covered clay particles dominate the flocculation processes. The different relative orientation of the clay-magnetite particles (edge-to-edge, face-to-edge, and face-to-face) are discussed in order to predict the most favored flocculi configuration.     

INDUCTION OF FREE RADICALS IN DNA BY PROFLAVINE AND VISIBLE LIGHT: INFLUENCE OF OXYGEN AND IONIC STRENGTH

Abstract —The photosensitization of native DNA is observed as an induction of free radicals in the DNA moiety of proflavine-DNA complexes. The intensity of the electron paramagnetic resonance spectra (at 77 K) is a measure of the number of free radicals present in frozen solutions of DNA-proflavine complexes after irradiation with visible light (Λ > 320 nm). In the absence of O₂, the photosensitization is significant but very low; it increases slightly with increasing NaCl ionic strength; it appears to be due to intercalated dye molecules and the qualitative analysis of the spectra obtained shows that mainly thymidine is involved. The reaction measured after saturation with O₂ is the same as the reaction in air but is quantitatively higher; the free radicals observed are peroxides. This induction of free radicals appears to be due to the intercalated dye molecules, each molecule acting independently. The important observation is a very sharp and large (around a hundred-fold) increase in the photosensitizing efficiency of the bound dye molecules occurring in NaCl between μ, # 0–25 and μ= 0–5 and in MgCl₂ between μ# 0–01 and μ=0–1.     

Simultaneous determination of concentration,diffusion coefficient and number of electrons for electroactive species by combining suitable electroanalytical measurements

The electroanalytical method described for the simultaneous determination of concentration, the number of electrons involved in the redox process and diffusion coefficient is based on evaluation of the ratios between the currents recorded for the analyte and for an easily standardized reference species dissolved in the same medium. Three different electroanalytical techniques are used in which the currents exhibit, for two techniques at least, different dependences on both the diffusion coefficient and electron number. The approach is applicable to diffusion-controlled processes, regardless of the degree of reversibility involved. Reliability tests with electroactive organic compounds dissolved in dimethyl sulphoxide show that both accuracy and precision are within 10% depending on the chosen combination of techniques.     

Electron transfer in proteins: nonorthogonal projections onto donor-acceptor subspace of the Hilbert space

We develop nonorthogonal projectors, called L?wdin projectors, to construct an effective donor-acceptor system composed of localized donor (D) and acceptor (A) states of a long-distance electron transfer problem. When these states have a nonvanishing overlap with the bridge states these projectors are non-Hermitian and there are various possible effective two-level systems that can be built. We show how these can be constructed directly from the Schr?dinger or Dyson equation projected onto the D-A subspace of the Hilbert space and explore these equations to determine the connection between Hamiltonian and Green function partitioning. We illustrate the use of these effective two-level systems in estimating the electron transfer rate in the context of a simple electron transfer model.     

Quantitative gas-liquid chromatography of iproniazid and iproclozide.

Analytically packed columns prepared with Versamid-930, Versamid-900, XE-60, and OV-225 as stationary phases were examined for quantitative gas-liquid chromatography of the potent monamine oxydase inhibitor (MAOI) drugs iproniazid and iproclozide. With the aid of chemically related substances as internal standards, response ratios were determined and linearities calculated by regression analysis. Using the 2-butyl analogs of compounds all four column systems permit quantitation of iproniazid and iproclozide with a percent standard deviation sigmaK of about 1% or less.